Pyrimidin-2-one compounds and their use as dopamine D3 receptor ligands

ABSTRACT

The invention relates to pyrimidin 2-one compounds of general formula (I), in addition to the derivatives and tautomers of (I) and the physiologically acceptable salts of said compounds. In said formula, A represents linear or branched C 3 -C 6  alkene, which can have a double bond or triple bond and/or a group Z, which is not adjacent to the nitrogen atom of the pyrimidinone ring and is selected from O, S, C(O), NR 3 , C(O)NR 3 , NR 3 C(O), OC(O) and C(O)O; B represents a group of the formula (II), in which X stands for CH 2  or N and Y stands for CH 2  or CH 2 CH 2 , or X—Y can also jointly represent C═CH, C═CH—CH 2  or CH—CH═CH; R 1  and R 2  are defined as cited in the description and the claims; and Ar represents an optionally substituted aromatic group. The invention also relates to a pharmaceutical agent, containing at least one compound (I) and the tautomers, derivatives and/or acid addition salts of said compound, optionally together with physiologically acceptable carriers and/or auxiliary agents. The invention also relates to the use of compounds of formula (I), and their tautomers, derivatives and pharmacologically acceptable acid addition salts for producing a pharmaceutical agent for treating diseases which respond to the influence of dopamine D 3  receptor ligands.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Section 371 application of PCT Application No. WO2004/080981, filed Mar. 12, 2004, which claims the priority of GermanPatent Application No. DE 10311065.8, filed Mar. 13, 2003.

The present invention relates to novel pyrimidin-2-one compounds. Thesecompounds have valuable therapeutic properties and are suitable inparticular for the treatment of disorders which respond to modulation ofthe dopamine D₃ receptor.

Neurons receive their information inter alia via G protein-coupledreceptors. There are numerous substances which exert their effect viathese receptors. One of these is dopamine. Confirmed findings about thepresence of dopamine and its physiological function as neurotransmitterhave been published. Disturbances in the dopaminergic transmitter systemresult in disorders of the central nervous system which include, forexample, schizophrenia, depression or Parkinson's disease. These andother disorders are treated with medicaments which interact with thedopamine receptors.

Until 1990, two subtypes of dopamine receptors were clearly definedpharmacologically, namely the D₁ and D₂ receptors. More recently, athird subtype has been found, namely the D₃ receptor, which appears tomediate some effects of antipsychotics and antiparkinsonian drugs (J. C.Schwartz et al., The Dopamine D₃ Receptor as a Target forAntipsychotics, in Novel Antipsychotic Drugs, H. Y. Meltzer, Ed. RavenPress, New York 1992, pages 135-144; M. Dooley et al., Drugs and Aging1998, 12, 495-514, J. N. Joyce, Pharmacology and Therapeutics 2001, 90,pp. 231-259 “The Dopamine D₃-Receptor as a Therapeutic Target forAntipsychotic and Antiparkinsonian Drugs”).

Dopamine receptors are now divided into two families. Firstly the D₂group consisting of D₂, D₃ and D₄ receptors, and secondly the D₁ groupconsisting of D₁ and D₅ receptors. Whereas D₁ and D₂ receptors arewidespread, the expression of D₃ receptors by contrast appears to beregioselective. Thus, these receptors are preferentially found in thelimbic system, the projecting regions of the mesolimbic dopamine system,especially in the nucleus accumbens, but also in other regions such asamygdala. Because of this comparatively regioselective expression, D₃receptors are regarded as a target with few side effects, and it isassumed that a selective D₃ ligand ought to have the properties of knownantipsychotics but not their dopamine D₂ receptor-mediated neurologicalside effects (P. Sokoloff et al., Localization and Function of the D₃Dopamine Receptor, Arzneim. Forsch./Drug Res. 42(1), 224 (1992); P.Sokoloff et al. Molecular Cloning and Characterization of a NovelDopamine Receptor (D₃) as a Target for Neuroleptics, Nature, 347, 146(1990)).

Pyrimidine compounds having dopamine D₃ receptor affinity are disclosedin DE 10131543 and WO 96/02519. Some of these compounds have highaffinities for the D₃ receptor. They are therefore proposed for thetreatment of disorders of the central nervous system.

There have been various reports that neuroleptics may lead to inhibitionof mitochondrial respiration. It has been shown that such an inhibitionis the cause of the neurotoxic effect of neuroleptics and of theirreversible extrapyramidal side effects which are observed on prolongedadministration of neuroleptics (see C. Burkhardt et al, Annals ofNeurology, Vol 33 (1993) 512-517; I. Maurer et al, Molecular andCellular Biochemistry 174 (1997) 225-229; S. Balijepalli et al,Neurochemistry International 38 (2001) 425-435). It is thereforedesirable to have selective dopamine D₃ receptor ligands which moreoverhave only a slight or no inhibitory effect on mitochondrial respiration.

The compounds ought in addition to show little plasma protein binding.The advantage of little plasma protein binding is that the compoundsshow better tolerability because the plasma level is more uniform anduncontrolled release of the active ingredient from plasma proteinbinding, for example as the result of increased physical activity orbecause of interactions with other medicaments, is avoided.

The invention is therefore based on the object of providing compoundswhich act as selective dopamine D₃ receptor ligands. These compoundsought additionally to lead to inhibition of mitochondrial respirationonly at high dosages or not at all. The compounds ought in addition toshow little plasma protein binding.

This object is achieved by pyrimidin-2-one compounds of the generalformula I

in which

-   A is linear or branched C3-C6-alkylene which may have a double bond    or a triple bond and/or a group Z which is not adjacent to the    nitrogen atom of the pyrimidinone ring and is selected from O, S,    C(O), NR³, C(O)NR³, NR³C(O), OC(O) and C(O)O-   B is a radical of the formula:

-   -   in which X is CH₂ or N, and Y is CH₂ or CH₂CH₂, or X—Y together        may also be C═CH, C═CH—CH₂ or CH—CH═CH, —

-   R¹, R² are independently of one another hydrogen, CN, NO₂, halogen,    OR^(3a), NR⁴R⁵, C(O)NR⁴R⁵, O—C(O)NR⁴R⁵, SR⁶, SOR⁶, SO₂R⁶, SO₂NR⁴R⁵,    COOR⁷, O—C(O)R⁸, COR⁸, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₂-C₆-alkenyl,    C₂-C₆-alkynyl, C₂-C₆-haloalkenyl, C₃-C₆-cycloalkyl,    -   5- or 6-membered heterocyclyl having 1, 2 or 3 heteroatoms        selected from O, S and N, which may be substituted by one or two        radicals which are selected independently of one another from        C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁴R⁵, CN, OH, C₁-C₂-fluoroalkyl or        halogen,    -   phenyl which may be substituted by one or two radicals which are        selected independently of one another from C₁-C₄-alkyl,        C₁-C₄-alkoxy, NR⁴R⁵, OH, CN, C₁-C₂-fluoroalkyl or halogen,    -   C₁-C₆-alkyl which is substituted by a radical selected from        OR^(3b), NR⁴R⁵, C(O)NR⁴R⁵, O—C(O)NR⁴R⁵, SR⁵, SOR⁶, SO₂R⁶,        SO₂NR⁴R⁵, COOR⁷, O—C(O)R⁸, COR⁸, C₃-C₆-cycloalkyl, 5- or        6-membered heterocyclyl having 1, 2 or 3 heteroatoms selected        from O, S and N, and phenyl, where phenyl and heterocyclyl in        turn may be substituted by one or two radicals which are        selected independently of one another from C₁-C₄-alkyl,        C₁-C₄-alkoxy, NR⁴R⁵, CN, OH, C₁-C₂-fluoroalkyl or halogen,    -   C₂-C₆-alkenyl which is substituted by a radical selected from        OR³, NR⁴R⁵, C(O)NR⁴R⁵, O—C(O)NR⁴R⁵, SR⁶, SOR⁶, SO₂R⁶, SO₂NR⁴R⁵,        COOR⁷, O—C(O)R⁸, COR⁸, C₃-C₆-cycloalkyl, 5- or 6-membered        heterocyclyl having 1, 2 or 3 heteroatoms selected from O, S and        N, and phenyl, where phenyl and heterocyclyl in turn may be        substituted by one or two radicals which are selected        independently of one another from C₁-C₄-alkyl, C₁-C₄-alkoxy,        NR⁴R⁵, OH, CN, C₁-C₂-fluoroalkyl or halogen,

-   Ar is an aromatic radical which is selected from phenyl, pyridyl,    pyrimidinyl and triazinyl, where the aromatic radical may have 1, 2    or 3 substituents which are selected independently of one another    from C₁-C₆-alkyl which is optionally substituted by OH,    C₁-C₄-alkoxy, halogen or phenyl, or C₂-C₆-alkenyl, C₂-C₆-alkynyl,    C₃-C₆-cycloalkyl, C₅-C₁₀-bicycloalkyl, C₆-C₁₀-tricycloalkyl, where    the last three groups mentioned may optionally be substituted by    halogen or C₁-C₄-alkyl, or halogen, CN, OR^(3c), NR⁴R⁵, NO₂, SR⁶,    SO₂R⁶, SO₂NR⁴R⁵, COOR⁷, COR⁸, 5- or 6-membered heterocyclyl having    1, 2 or 3 heteroatoms selected from O, S and N, and phenyl, where    phenyl and heterocyclyl optionally have one or two substituents    which are selected independently of one another from C₁-C₄-alkyl,    C₁-C₄-alkoxy, NR⁴R⁵, CN, C₁-C₂-fluoroalkyl and halogen, and where 2    substituents bonded to adjacent C atoms of the aromatic radical may    together be C₃- or C₄-alkylene, or may together with the C atoms to    which they are bonded be a fused-on, unsaturated 5 or 6-membered    carbocycle or a 5- or 6-membered heterocycle having 1 or 2 nitrogen    atoms as ring members,

-   R³, R^(3a), R^(3b), R^(3c), R^(3d), R⁴, R⁵, R⁶, R⁷ and R⁸ are    independently of one another H, C₁-C₆-alkyl which is optionally    substituted by OH, C₁-C₄-alkoxy or phenyl, or C₁-C₆-haloalkyl or    phenyl, where R⁵ may also be a group COR⁹ where R⁹ is hydrogen,    C₁-C₄-alkyl or phenyl which is optionally substituted by one or two    radicals which are selected independently of one another from    C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁴R⁵, CN, C₁-C₂-fluoroalkyl or halogen,    where

-   R⁴ with R⁵ may also form together with the nitrogen atom to which    they are bonded a 4-, 5- or 6-membered saturated or unsaturated    heterocycle which may optionally have a further heteroatom selected    from O, S and NR¹⁰ as ring member, where R¹⁰ is hydrogen or    C₁-C₄-alkyl, and where the heterocycle may optionally carry 1, 2, 3    or 4 C₁-C₄-alkyl groups,    and the derivatives and tautomers of the formulae Ia or Ib

-   -   in which R is hydrogen or C₁-C₄-alkyl, and Q is halogen or a        group OR^(3d), and A, B, Ar and R² have the aforementioned        meanings, and by the physiologically tolerated salts of these        compounds.

The present invention therefore relates to pyrimidine compounds of thegeneral formula I and to the derivatives and tantomers of the formulaeIa and Ib, and the physiologically acceptable salts thereof.

The present compound additionally relates to a pharmaceuticalcomposition comprising at least one compound of the formulae I, Iaand/or Ib and/or the physiologically acceptable acid addition saltsthereof and, where appropriate, one or more physiologically acceptablecarriers.

The present invention also relates to the use of a pyrimidinone compoundof the formula I, of the derivatives and tantomers thereof of theformulae Ia and Ib and of the salts thereof for producing apharmaceutical composition for the treatment of disorders which respondto modulation by dopamine D₃ receptor ligands.

The disorders which respond to modulation by dopamine D₃ receptorligands include for example impairments and disorders of the centralnervous system, especially schizophrenia and depression, Parkinson's andepilepsy, and additionally addictive disorders and impairments of renalfunction.

The aforementioned indications are treated by using according to theinvention at least one compound of the general formulae I, Ia and/or Ibwith the meanings specified at the outset. If the compounds of theformula I have one or more centers of asymmetry, it is also possible toemploy mixture of enantiomers, especially racemates, mixtures ofdiastereomers, mixtures of tautomers, but preferably the respectivesubstantially pure enantiomers, diastereomers and tautomers.

It is likewise possible to use physiologically tolerated salts of thecompounds of the formulae I, Ia and Ib especially acid addition saltswith physiologically tolerated acids. Examples of suitablephysiologically tolerated organic and inorganic acids are hydrochloricacid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid,maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid orbenzoic acid. Further acids which can be used are described inFortschritte der Arzneimittelforschung, Volume 10, pages 224 et seq.,Birkhäuser Verlag, Basle and Stuttgart, 1966.

Halogen here and hereinafter is fluorine, chlorine, bromine or iodine.

C_(n)-C_(m)-Alkyl (also in radicals such as alkoxy, alkylthio,alkylamino etc.) means a straight-chain or branched alkyl group having nto m carbon atoms, e.g. 1 to 6 carbon atoms and in particular 1 to 4carbon atoms. Examples of an alkyl group are methyl, ethyl, n-propyl,isopropyl, n-butyl, 2-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl,neopentyl, n-hexyl and the like.

The alkyl group may have one or more substituents which are selectedindependently of one another from OH, C₁-C₄-alkoxy, halogen or phenyl.In the case of a halogen substituent, the alkyl group may include inparticular 1, 2, 3 or 4 halogen atoms which may be present on one ormore C atoms, preferably in the α- or ω-position. Groups of this typeare also referred to hereinafter as haloalkyl. A preferred haloalkyl isC₁-C₂-fluoroalkyl or C₁-C₂-fluorochloroalkyl, in particular CF₃, CHF₂,CF₂Cl, CH₂F, CH₂CF₃.

In the case of hydroxy-substituted alkyl, the alkyl group has inparticular one hydroxy group, such as, for example, hydroxymethyl,2-hydroxyeth-1-yl, 2-hydroxyprop-1-yl, 3-hydroxyprop-1-yl,1-hydroxyprop-2-yl, 2-hydroxybut-1-yl, 3-hydroxybut-1-yl,4-hydroxy-but-1-yl, 1-hydroxybut-2-yl, 1-hydroxybut-3-yl,2-hydroxybut-3-yl, 1-hydroxy-2-methylprop-3-yl,2-hydroxy-2-methylprop-3-yl or 2-hydroxymethylprop-2-yl, in particular2-hydroxyethyl.

In the case of alkoxy-substituted alkyl, the alkyl group has inparticular one alkoxy substituent. These radicals are referred to,depending on the number of carbon atoms, also asC_(n)-C_(m)-alkoxy-C_(n)-C_(m)-alkyl and are, for example,methoxymethyl, ethoxymethyl, 2-methoxyethyl, 1-methoxyethyl,2-ethoxyethyl, 1-ethoxyethyl, n-propoxymethyl, isopropoxymethyl,n-butoxymethyl, (1-methylpropoxy)methyl, (2-methylpropoxy)methyl,CH₂—OC(CH₃)₃, 2-(methoxy)ethyl, 2-(ethoxy)ethyl, 2-(n-propoxy)ethyl,2-(1-methylethoxy)ethyl, 2-(n-butoxy)ethyl, 2-(1-methylpropoxy)ethyl,2-(2-methylpropoxy)ethyl, 2-(1,1-dimethylethoxy)ethyl,2-(methoxy)propyl, 2-(ethoxy)propyl, 2-(n-propoxy)propyl,2-(1-methylethoxy)propyl, 2-(n-butoxy)propyl, 2-(1-methylpropoxy)propyl,2-(2-methylpropoxy)propyl, 2-(1,1-dimethylethoxy)propyl,3-(methoxy)propyl, 3-(ethoxy)propyl, 3-(n-propoxy)propyl,3-(1-methylethoxy)propyl, 3-(n-butoxy)/propyl,3-(1-methylpropoxy)-propyl, 3-(2-methylpropoxy)propyl,3-(1,1-dimethylethoxy)propyl, 2-(methoxy)butyl, 2-(ethoxy)butyl,2-(n-propoxy)butyl, 2-(1-methylethoxy)butyl, 2-(n-butoxy)butyl,2-(1-methylpropoxy)butyl, 2-(2-methylpropoxy)butyl,2-(1,1-dimethylethoxy)butyl, 3-(methoxy)butyl, 3-(ethoxy)butyl,3-(n-propoxy)butyl, 3-(1-methylethoxy)butyl, 3-(n-butoxy)butyl,3-(1-methylpropoxy)butyl, 3-(2-methylpropoxy)butyl,3-(1,1-dimethylethoxy)butyl, 4-(methoxy)butyl, 4-(ethoxy)butyl,4-(n-propoxy)butyl, 4-(1-methylethoxy)butyl, 4-(n-butoxy)butyl,4-(1-methylpropoxy)butyl, 4-(2-methylpropoxy)butyl or4-(1,1-dimethylethoxy)butyl, preferably methoxymethyl, ethoxymethyl,2-methoxyethyl, 2-ethoxyethyl, 2-(methoxy)propyl, 2-(ethoxy)propyl or3-(methoxy)propyl, 3-(ethoxy)-propyl.

Cycloalkyl is in particular C₃-C₆-cycloalkyl such as cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

The term “alkylene” includes in principle straight-chain or branchedradicals preferably having 3 to 10 and particularly preferably having 3to 8 carbon atoms, such as prop-1,2-ylene, prop-1,3-ylene,but-1,2-ylene, but-1,3-ylene, but-1,4-ylene, 2-methylprop-1,3-ylene,pent-1,2-ylene, pent-1,3-ylene, pent-1,4-ylene, pent-1,5-ylene,pent-2,3-ylene, pent-2,4-ylene, 1-methylbut-1,4-ylene,2-methylbut-1,4-ylene, hex-1,3-ylene, hex-2,4-ylene, hex-1,4-ylene,hex-1,5-ylene, hex-1,6-ylene and the like. C₀-Alkylene is a single bond,C₁-alkylene is methylene and C₂-alkylene is 1,1-ethylene or1,2-ethylene.

4, 5- or 6-membered heterocyclyl includes both aromatic heterocyclyl(hetaryl or heteroaryl) and completely saturated or partiallyunsaturated heterocyclic radicals.

Heterocyclyl has 1, 2 or 3 heteroatoms selected from O, S and N, e.g. 1,2 or 3 nitrogen atoms, 1 or 2 oxygen atoms, or 1 oxygen atom and 1 or 2nitrogen atoms or 1 sulfur atom and 1 or 2 nitrogen atoms.

Heterocyclyl may be unsubstituted or have 1 or 2 substituents selectedfrom C₁-C₄-alkyl, C₁-C₄-alkoxy, OH, CN, NR⁴R⁵, C₁-C₂-fluoroalkyl andhalogen. Heterocyclyl may additionally have a fused-on 5- or 6-memberedcarbocycle, e.g. a benzene, cyclopentane or cyclohexene ring or afused-on heterocycle, e.g. a fused-on pyrrolyfuran, thiophene, thiazole,pyridine, pyrimidine or pyridazine ring.

Examples of saturated heterocyclyl are azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, oxolanyl, 1,3-dioxolanyl, 1,3-and 1,4-dioxanyl, 1,3-oxothiolanyl, oxazolidinyl and the like.

Examples of “5- or 6-membered aromatic heterocyclic radicals” which have1, 2 or 3 heteroatoms which are selected from O, S and N are inparticular pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl,pyrrolyl, pyrazolyl, thienyl, furanyl, oxazolyl, thiazolyl, isoxazolyl,tetrazolyl, thiadiazolyl and triazolyl. These may have 1 or 2 of theaforementioned substituents on the nitrogen atoms and on the carbonatoms. Where one of the substituents is hydroxy, the radicals may alsoexist in a tautomeric form having a carbonyl group. Examples of 5- or6-membered heterocyclic radicals which have a fused-on carbocycleinclude benzofuranyl, benzthienyl, indolyl, benzothiazolyl,benzoxazolyl, benzimidazolyl, benzopyrazolyl, quinolinyl, isoquinolinyl,quinoxalinyl, quinazolinyl, cinnolinyl, and corresponding partiallyhydrogenated groups.

Examples of a fused-on 5 or 6-membered carbocycle are cyclopentene,cyclopentadiene, cyclohexene, cyclohexadiene and benzene. Examples of afused-on 5- or 6-membered heterocycle having 1 or 2 nitrogen atoms asring members are pyridine, 1,2,3,4- and 1,2,5,6-tetrahydropyridine, 1,2-and 1,4-dihydrophyridine, pyrimidine, pyrazine and pyridazine.

In group A, the two binding sites of the alkylene chain are preferablylocated not on the same atom but form, where appropriate with the groupZ, a chain which has at least three and preferably at least four membersand which separates the pyrimidin-2-one ring from the nitrogen atom ofthe (partially) saturated nitrogen heterocycle B by at least 4 andpreferably by at least 5 bonds from one another. If A has no group Z,then A includes 3 to 6 carbon atoms and preferably 4 or 5 andspecifically 4 carbon atoms. If A has at least one of said groups Z, Aincludes 3 to 6, in particular 3 or 4, carbon atoms and the group Z.Preferred groups Z are O, S and NR³. The heteroatoms of group Z areordinarily not bonded either to the nitrogen atom of the pyrimidin-2-onering or to the nitrogen atom of group B. The saturated bonds in alkylenemay be replaced by unsaturated bonds (alkenylene; alkynylene). This canresult in straight-chain or branched unsaturated groups A in which thenumber and arrangement of the carbon atoms corresponds to that of theaforementioned alkylene radicals, but where one or more single bonds arereplaced by corresponding unsaturated double or triple bonds.

With a view to the use of the compounds of the invention as dopamine D₃receptor ligands, the variables A, B, R¹, R² and Ar preferably have,independently of one another, the meanings indicated below:

-   A is linear or branched C₃-C₆-alkylene which includes no group Z,    where alkylene may have a double bond. In particularly preferred    compounds of the formula I, A is —(CH₂)_(n), in which n is 4, 5 or 6    and in particular 4, or A is trans-CH₂—CH═CH—CH₂—,    trans-CH₂—C(CH₃)═CH—CH₂—, —CH₂—CH(CH₃)—CH₂—CH₂— or    —CH₂—CH₂—CH₂—CH(CH₃)—. A is particularly preferably —(CH₂)₄—;-   B is a bivalent radical of the general formulae:

-   -   the nitrogen atom therein is linked to group A. B is in        particular piperazine-1,4-diyl.

-   R¹ is a group OR^(3a), NR⁴R⁵, SR⁶, C₃-C₆-cycloalkyl, C₁-C₄-alkyl    which is optionally substituted by OH, C₁-C₄-alkoxy, halogen or    phenyl, or is 5- or 6-membered aromatic heterocyclyl having 1, 2 or    3 heteroatoms selected from O, S and N, which may be substituted by    one or two radicals which are selected independently of one another    from C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁴R⁵, CN, OH, C₁-C₂-fluoroalkyl or    halogen, or is phenyl which may be substituted by one or two    radicals which are selected independently of one another from    C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁴R⁵, OH, CN, C₁-C₂-fluoroalkyl or    halogen.    -   R¹ is in particular C₁-C₄-alkyl, halogen, optionally substituted        phenyl, C₁-C₂-fluoroalkyl, a group OR^(3a), a group SR⁶ or a        radical NR⁴R⁵. In this connection, R^(3a) is in particular        hydrogen, C₁-C₄-alkyl, phenyl or benzyl and specifically        hydrogen. R⁴ is preferably hydrogen or alkyl. R⁵ is preferably        hydrogen, C₁-C₄-alkyl, phenyl or benzyl or forms together with        the nitrogen atom and the radical R⁴ a 4-, 5- or 6-membered        saturated heterocycle such as azetidinyl, pyrrolidinyl,        piperidinyl, morpholinyl or piperazinyl. R⁶ is in this        connection preferably hydrogen, C₁-C₄-alkyl, phenyl or benzyl        and in particular hydrogen. Substituted phenyl means in this        connection that the phenyl radical may be substituted by one or        two radicals, e.g. by C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁴R⁵, OH, CN,        C₁-C₂-fluoroalkyl and/or halogen.    -   In a particularly preferred embodiment of the invention, R¹ is        C₁-C₄-alkyl, in particular methyl, trifluoromethyl or a radical        OR^(3a). R^(3a) therein has the aforementioned meanings and is        in particular H, C₁-C₄-alkyl, phenyl or benzyl and        specifically H. In this connection, the phenyl ring in phenyl        and in benzyl may be substituted by one or two radicals which        are selected independently of one another from C₁-C₄-alkyl,        C₁-C₄-alkoxy, NR⁴R⁵, OH, CN, C₁-C₂-fluoroalkyl or halogen.

-   R² is preferably disposed in position 5 of the pyrimidin-2-one ring.    R² is in particular selected from H, C₁-C₄-alkyl, C₁-C₂-fluoroalkyl,    halogen and cyano, specifically from H, methyl, CN, fluorine and    trifluoromethyl. In a particularly preferred embodiment, R² is    C₁-C₄-alkyl, in particular methyl. In another particularly preferred    embodiment, R² is hydrogen.

A very particularly preferred embodiment of the invention relates tocompounds of the formula I in which R¹ is OR^(3a) and in particular OH,and R² is selected in particular from H, fluorine, chlorine, CN andC₁-C₄-alkyl and specifically hydrogen or methyl.

A further very particularly preferred embodiment of the inventionrelates to compounds of the formula I in which R¹ is methyl, and R² isselected in particular from H, fluorine, chlorine, CN and C₁-C₄-alkyland specifically is hydrogen.

Ar is preferably a radical of the general formula:

in which at least one of the variables D¹ to D³ is N and the othervariables D¹ to D³ are CH, and R^(a) and R^(b) have the meaningsindicated above as substituents on Ar, or are hydrogen. Among these,preferred compounds are those in which D¹ and D² are each nitrogen, andD³ is CH. R^(a) and R^(b) are preferably independently of one anotherthe following groups: hydrogen, OR^(3b), NR⁴R⁵, CN, C₁-C₆-alkyl which isoptionally substituted by OH, C₁-C₄-alkoxy, halogen or phenyl, orC₂-C₆-alkenyl, C₂-C₆-alkynyl, C₅-C₆-cycloalkyl, C₅-C₁₀-bicycloalkyl,C₆-C₁₀-tricycloalkyl, where the last three groups mentioned mayoptionally be substituted by halogen or C₁-C₄-alkyl, or halogen, CN,OR^(3c),5- or 6-membered heterocyclyl having 1, 2 or 3 heteroatomsselected from O, S and N, and phenyl, where phenyl and heterocyclyloptionally have one or two substituents which are selected independentlyof one another from C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁴R⁵, CN,C₁-C₂-fluoroalkyl and halogen. Preferably at least one of the radicalsR^(a), R^(b) and in particular both radicals R^(a), R^(b) is/aredifferent from hydrogen. R^(b) is in particular C₁-C₆-alkyl,particularly preferably branched C₃-C₆-alkyl and specificallytert-butyl. R^(a) is preferably selected from C₁-C₄-alkyl,C₃-C₆-cycloalkyl and C₁-C₂-fluoroalkyl and very particularly preferablyfrom CF₃, cyclopentyl and n-propyl. It is particularly preferred forR^(a) and R^(b) together to have the meanings indicated as preferred.

Where Ar has a fused-on ring, Ar is preferably a radical of the formula:

in which D⁴, D⁵ and D⁵ are independently of one another CH or N, Q islinear C₃-C₄-alkylene, C₃-C₄-alkenylene or a group CH═CH—N═CH orN═CH—CH═CH, m is 0, 1 or 2, and R is a substituent different fromhydrogen, such as C₁-C₄-alkyl, C₁-C₄-alkoxy, CN, OH, halogen or NR⁴R⁵.

Among the pyrimidin-2-one compounds of the invention, preference isgiven to the pyrimidinone compounds of the general formula I.1

in which Ar, R¹ and R² have the aforementioned meanings and inparticular the meanings indicated as preferred, and A′ is a group—(CH₂)_(n) in which n is 3, 4, 5 or 6 and in particular 4, or A′ is oneof the following groups: trans-CH₂—CH═CH—CH₂—, trans-CH₂—C(CH₃)═CH—CH₂—,—CH₂—CH(CH₃)—CH₂—CH₂— or —CH₂—CH₂—CH₂—CH(CH₃)—.

Preference is likewise given to the derivatives and tautomers of theformulae Ia.1 or Ib.1

in which R, A′, O, Ar and R² have the aforementioned meanings and inparticular the meanings indicated as preferred.

Otherwise, the groups R³, R^(3b), R^(3c), R^(3d), R⁴, R⁵, R⁶, R⁷ and R⁸preferably have the meanings indicated below:

R³ is preferably H, C₁-C₄-alkyl, phenyl-substituted C₁-C₄-alkyl orCOR¹¹. R¹¹ therein has the meanings indicated for R⁸ and is inparticular C₁-C₄-alkyl. R³ in groups NR³ is preferably H, C₁-C₄-alkyl,phenyl-substituted C₁-C₄-alkyl or COR¹¹. NR³ is particularly preferablyNH, NCH₃, NCOCH₃ or NCH₂-phenyl. R³ in the groups C(O)NR³ and NR³C(O) ispreferably H, C₁-C₄-alkyl, phenyl-substituted C₁-C₄-alkyl or COR¹¹.C(O)NR³ is particularly preferably CONH, CONCH₃ or CONCH₂-phenyl.NR³C(O) is particularly preferably NHCO, NCH₃CO or N(CH₂-phenyl)CO.

R^(3b), R^(3c) and R^(3d) are independently of one another preferably H,C₁-C₄-alkyl, CF₃, CHF₂ or phenyl. OR^(3b), OR^(3c) and OR^(3d) areparticularly preferably methoxy, trifluoromethoxy or phenoxy.

R⁴ is preferably hydrogen or alkyl. R⁵ is preferably hydrogen,C₁-C₄-alkyl, phenyl, benzyl or a group COR¹¹. R⁴ is preferably H orC₁-C₄-alkyl, and R⁵ is preferably H, C₁-C₄-alkyl or COR¹¹ in substituentCONR⁴R⁵. CONR⁴R⁵ is particularly preferably CONH₂, CONHCH₃, CON(CH₃)₂ orC(O)NHC(O)CH₃. R⁴ is preferably H, C₁-C₄-alkyl or phenyl-substitutedC₁-C₄-alkyl, and R⁵ is H, C₁-C₄-alkyl or COR¹¹ in substituent NR⁴R⁵.NR⁴R⁵ is particularly preferably NH₂, NHCH₃, N(CH₃)₂, NH-benzyl orNHCOCH₃. R⁴ is preferably H or C₁-C₄-alkyl, and R⁵ is preferably H,C₁-C₄-alkyl or COR¹¹ in substituent SO₂NR⁴R⁵. SO₂NR⁴R⁵ is particularlypreferably sulfamoyl. R⁴ and R⁵ in the aforementioned groups may alsoform together with the nitrogen atom to which they are bonded asaturated or unsaturated 4-, 5- or 6-membered, preferably saturatednitrogen heterocycle which may have a further heteroatom such as N, S orO, and which may be substituted by 1, 2, 3 or 4 alkyl groups. Examplesof such heterocycles are piperidinyl, morpholinyl, pyrrolidinyl,4-methylpiperazinyl and 4-methylpiperidinyl.

R⁶ is preferably H, C₁-C₄-alkyl, phenyl or benzyl. R⁶ in substituent SR⁶is preferably H, C₁-C₄-alkyl, phenyl or benzyl. R⁶ in substituent SOR⁶is preferably phenyl or C₁-C₄-alkyl. R⁵ in substituent SO₂R⁶ ispreferably H or C₁-C₄-alkyl. SO₂R⁶ is particularly preferablymethylsulfonyl.

R⁷ in substituent COOR⁷ is H or C₁-C₄-alkyl. COOR⁷ is particularlypreferably C₁-C₄-alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl ort-butoxycarbonyl.

R⁸ in substituents COR⁸ and OC(O)R⁸ is preferably H, C₁-C₄-alkyl orphenyl. COR⁸ is particularly preferably formyl, acetyl or benzoyl.

Among the compounds of the general formula I.1, particularly preferredcompounds are those of the general formula I.1a,

in which A′, R¹, R² and R^(a) have the meanings indicated above,especially the meanings indicated as preferred. Examples of suchcompounds are compounds I.1a.1 to I.1a.871 which are listed in Table 1below and where the variables A′, R¹, R² and R^(a) in each case jointlyhave the meaning indicated in one line of Table 1.

TABLE 1 R¹ R² A′ R^(a) 1. OH H —(CH₂)₄— CF₃ 2. OH CH₃ —(CH₂)₄— CF₃ 3.CH₃ H —(CH₂)₄— CF₃ 4. C(CH₃)₃ H —(CH₂)₄— CF₃ 5. C₆H₅ H —(CH₂)₄— CF₃ 6.C₆H₅ CH₃ —(CH₂)₄— CF₃ 7. CF₃ H —(CH₂)₄— CF₃ 8. OH F —(CH₂)₄— CF₃ 9. OHCN —(CH₂)₄— CF₃ 10. N(CH₃)₂ H —(CH₂)₄— CF₃ 11. N(CH₃)₂ CH₃ —(CH₂)₄— CF₃12. OH H trans —CH₂—CH═CH—CH₂— CF₃ 13. OH CH₃ trans —CH₂—CH═CH—CH₂— CF₃14. CH₃ H trans —CH₂—CH═CH—CH₂— CF₃ 15. C(CH₃)₃ H trans —CH₂—CH═CH—CH₂—CF₃ 16. C₆H₅ H trans —CH₂—CH═CH—CH₂— CF₃ 17. C₆H₅ CH₃ trans—CH₂—CH═CH—CH₂— CF₃ 18. CF₃ H trans —CH₂—CH═CH—CH₂— CF₃ 19. OH F trans—CH₂—CH═CH—CH₂— CF₃ 20. OH CN trans —CH₂—CH═CH—CH₂— CF₃ 21. N(CH₃)₂ Htrans —CH₂—CH═CH—CH₂— CF₃ 22. N(CH₃)₂ CH₃ trans —CH₂—CH═CH—CH₂— CF₃ 23.OH H trans —CH₂—C(CH₃)═CH—CH₂— CF₃ 24. OH CH₃ trans —CH₂—C(CH₃)═CH—CH₂—CF₃ 25. CH₃ H trans —CH₂—C(CH₃)═CH—CH₂— CF₃ 26. C(CH₃)₃ H trans—CH₂—C(CH₃)═CH—CH₂— CF₃ 27. C₆H₅ H trans —CH₂—C(CH₃)═CH—CH₂— CF₃ 28.C₆H₅ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CF₃ 29. CF₃ H trans—CH₂—C(CH₃)═CH—CH₂— CF₃ 30. OH F trans —CH₂—C(CH₃)═CH—CH₂— CF₃ 31. OH CNtrans —CH₂—C(CH₃)═CH—CH₂— CF₃ 32. N(CH₃)₂ H trans —CH₂—C(CH₃)═CH—CH₂—CF₃ 33. N(CH₃)₂ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CF₃ 34. OH H—CH₂—CH(CH₃)—CH₂—CH₂— CF₃ 35. OH CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— CF₃ 36. CH₃ H—CH₂—CH(CH₃)—CH₂—CH₂— CF₃ 37. C(CH₃)₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CF₃ 38.C₆H₅ H —CH₂—CH(CH₃)—CH₂—CH₂— CF₃ 39. C₆H₅ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— CF₃40. CF₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CF₃ 41. OH F —CH₂—CH(CH₃)—CH₂—CH₂— CF₃42. OH CN —CH₂—CH(CH₃)—CH₂—CH₂— CF₃ 43. N(CH₃)₂ H —CH₂—CH(CH₃)—CH₂—CH₂—CF₃ 44. N(CH₃)₂ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— CF₃ 45. OH H—CH₂—CH₂—CH₂—CH(CH₃)— CF₃ 46. OH CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CF₃ 47. CH₃ H—CH₂—CH₂—CH₂—CH(CH₃)— CF₃ 48. C(CH₃)₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CF₃ 49.C₆H₅ H —CH₂—CH₂—CH₂—CH(CH₃)— CF₃ 50. C₆H₅ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CF₃51. CF₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CF₃ 52. OH F —CH₂—CH₂—CH₂—CH(CH₃)— CF₃53. OH CN —CH₂—CH₂—CH₂—CH(CH₃)— CF₃ 54. N(CH₃)₂ H —CH₂—CH₂—CH₂—CH(CH₃)—CF₃ 55. N(CH₃)₂ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CF₃ 56. OH H —(CH₂)₄— CHF₂ 57.OH CH₃ —(CH₂)₄— CHF₂ 58. CH₃ H —(CH₂)₄— CHF₂ 59. C(CH₃)₃ H —(CH₂)₄— CHF₂60. C₆H₅ H —(CH₂)₄— CHF₂ 61. C₆H₅ CH₃ —(CH₂)₄— CHF₂ 62. CF₃ H —(CH₂)₄—CHF₂ 63. OH F —(CH₂)₄— CHF₂ 64. OH CN —(CH₂)₄— CHF₂ 65. N(CH₃)₂ H—(CH₂)₄— CHF₂ 66. N(CH₃)₂ CH₃ —(CH₂)₄— CHF₂ 67. OH H trans—CH₂—CH═CH—CH₂— CHF₂ 68. OH CH₃ trans —CH₂—CH═CH—CH₂— CHF₂ 69. CH₃ Htrans —CH₂—CH═CH—CH₂— CHF₂ 70. C(CH₃)₃ H trans —CH₂—CH═CH—CH₂— CHF₂ 71.C₆H₅ H trans —CH₂—CH═CH—CH₂— CHF₂ 72. C₆H₅ CH₃ trans —CH₂—CH═CH—CH₂—CHF₂ 73. CF₃ H trans —CH₂—CH═CH—CH₂— CHF₂ 74. OH F trans —CH₂—CH═CH—CH₂—CHF₂ 75. OH CN trans —CH₂—CH═CH—CH₂— CHF₂ 76. N(CH₃)₂ H trans—CH₂—CH═CH—CH₂— CHF₂ 77. N(CH₃)₂ CH₃ trans —CH₂—CH═CH—CH₂— CHF₂ 78. OH Htrans —CH₂—C(CH₃)═CH—CH₂— CHF₂ 79. OH CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CHF₂80. CH₃ H trans —CH₂—C(CH₃)═CH—CH₂— CHF₂ 81. C(CH₃)₃ H trans—CH₂—C(CH₃)═CH—CH₂— CHF₂ 82. C₆H₅ H trans —CH₂—C(CH₃)═CH—CH₂— CHF₂ 83.C₆H₅ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CHF₂ 84. CF₃ H trans—CH₂—C(CH₃)═CH—CH₂— CHF₂ 85. OH F trans —CH₂—C(CH₃)═CH—CH₂— CHF₂ 86. OHCN trans —CH₂—C(CH₃)═CH—CH₂— CHF₂ 87. N(CH₃)₂ H trans—CH₂—C(CH₃)═CH—CH₂— CHF₂ 88. N(CH₃)₂ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CHF₂89. OH H —CH₂—CH(CH₃)—CH₂—CH₂— CHF₂ 90. OH CH₃ —CH₂—CH(CH₃)—CH₂—CH₂—CHF₂ 91. CH₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CHF₂ 92. C(CH₃)₃ H—CH₂—CH(CH₃)—CH₂—CH₂— CHF₂ 93. C₆H₅ H —CH₂—CH(CH₃)—CH₂—CH₂— CHF₂ 94.C₆H₅ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— CHF₂ 95. CF₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CHF₂96. OH F —CH₂—CH(CH₃)—CH₂—CH₂— CHF₂ 97. OH CN —CH₂—CH(CH₃)—CH₂—CH₂— CHF₂98. N(CH₃)₂ H —CH₂—CH(CH₃)—CH₂—CH₂— CHF₂ 99. N(CH₃)₂ CH₃—CH₂—CH(CH₃)—CH₂—CH₂— CHF₂ 100. OH H —CH₂—CH₂—CH₂—CH(CH₃)— CHF₂ 101. OHCH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CHF₂ 102. CH₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CHF₂103. C(CH₃)₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CHF₂ 104. C₆H₅ H—CH₂—CH₂—CH₂—CH(CH₃)— CHF₂ 105. C₆H₅ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CHF₂ 106.CF₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CHF₂ 107. OH F —CH₂—CH₂—CH₂—CH(CH₃)— CHF₂108. OH CN —CH₂—CH₂—CH₂—CH(CH₃)— CHF₂ 109. N(CH₃)₂ H—CH₂—CH₂—CH₂—CH(CH₃)— CHF₂ 110. N(CH₃)₂ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CHF₂111. OH H —(CH₂)₄— C₆H₅ 112. OH CH₃ —(CH₂)₄— C₆H₅ 113. CH₃ H —(CH₂)₄—C₆H₅ 114. C(CH₃)₃ H —(CH₂)₄— C₆H₅ 115. C₆H₅ H —(CH₂)₄— C₆H₅ 116. C₆H₅CH₃ —(CH₂)₄— C₆H₅ 117. CF₃ H —(CH₂)₄— C₆H₅ 118. OH F —(CH₂)₄— C₆H₅ 119.OH CN —(CH₂)₄— C₆H₅ 120. N(CH₃)₂ H —(CH₂)₄— C₆H₅ 121. N(CH₃)₂ CH₃—(CH₂)₄— C₆H₅ 122. OH H trans —CH₂—CH═CH—CH₂— C₆H₅ 123. OH CH₃ trans—CH₂—CH═CH—CH₂— C₆H₅ 124. CH₃ H trans —CH₂—CH═CH—CH₂— C₆H₅ 125. C(CH₃)₃H trans —CH₂—CH═CH—CH₂— C₆H₅ 126. C₆H₅ H trans —CH₂—CH═CH—CH₂— C₆H₅ 127.C₆H₅ CH₃ trans —CH₂—CH═CH—CH₂— C₆H₅ 128. CF₃ H trans —CH₂—CH═CH—CH₂—C₆H₅ 129. OH F trans —CH₂—CH═CH—CH₂— C₆H₅ 130. OH CN trans—CH₂—CH═CH—CH₂— C₆H₅ 131. N(CH₃)₂ H trans —CH₂—CH═CH—CH₂— C₆H₅ 132.N(CH₃)₂ CH₃ trans —CH₂—CH═CH—CH₂— C₆H₅ 133. OH H trans—CH₂—C(CH₃)═CH—CH₂— C₆H₅ 134. OH CH₃ trans —CH₂—C(CH₃)═CH—CH₂— C₆H₅ 135.CH₃ H trans —CH₂—C(CH₃)═CH—CH₂— C₆H₅ 136. C(CH₃)₃ H trans—CH₂—C(CH₃)═CH—CH₂— C₆H₅ 137. C₆H₅ H trans —CH₂—C(CH₃)═CH—CH₂— C₆H₅ 138.C₆H₅ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— C₆H₅ 139. CF₃ H trans—CH₂—C(CH₃)═CH—CH₂— C₆H₅ 140. OH F trans —CH₂—C(CH₃)═CH—CH₂— C₆H₅ 141.OH CN trans —CH₂—C(CH₃)═CH—CH₂— C₆H₅ 142. N(CH₃)₂ H trans—CH₂—C(CH₃)═CH—CH₂— C₆H₅ 143. N(CH₃)₂ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— C₆H₅144. OH H —CH₂—CH(CH₃)—CH₂—CH₂— C₆H₅ 145. OH CH₃ —CH₂—CH(CH₃)—CH₂—CH₂—C₆H₅ 146. CH₃ H —CH₂—CH(CH₃)—CH₂—CH₂— C₆H₅ 147. C(CH₃)₃ H—CH₂—CH(CH₃)—CH₂—CH₂— C₆H₅ 148. C₆H₅ H —CH₂—CH(CH₃)—CH₂—CH₂— C₆H₅ 149.C₆H₅ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— C₆H₅ 150. CF₃ H —CH₂—CH(CH₃)—CH₂—CH₂—C₆H₅ 151. OH F —CH₂—CH(CH₃)—CH₂—CH₂— C₆H₅ 152. OH CN—CH₂—CH(CH₃)—CH₂—CH₂— C₆H₅ 153. N(CH₃)₂ H —CH₂—CH(CH₃)—CH₂—CH₂— C₆H₅154. N(CH₃)₂ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— C₆H₅ 155. OH H—CH₂—CH₂—CH₂—CH(CH₃)— C₆H₅ 156. OH CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— C₆H₅ 157.CH₃ H —CH₂—CH₂—CH₂—CH(CH₃)— C₆H₅ 158. C(CH₃)₃ H —CH₂—CH₂—CH₂—CH(CH₃)—C₆H₅ 159. C₆H₅ H —CH₂—CH₂—CH₂—CH(CH₃)— C₆H₅ 160. C₆H₅ CH₃—CH₂—CH₂—CH₂—CH(CH₃)— C₆H₅ 161. CF₃ H —CH₂—CH₂—CH₂—CH(CH₃)— C₆H₅ 162. OHF —CH₂—CH₂—CH₂—CH(CH₃)— C₆H₅ 163. OH CN —CH₂—CH₂—CH₂—CH(CH₃)— C₆H₅ 164.N(CH₃)₂ H —CH₂—CH₂—CH₂—CH(CH₃)— C₆H₅ 165. N(CH₃)₂ CH₃—CH₂—CH₂—CH₂—CH(CH₃)— C₆H₅ 166. OH H —(CH₂)₄— C(CH₃)₃ 167. OH CH₃—(CH₂)₄— C(CH₃)₃ 168. CH₃ H —(CH₂)₄— C(CH₃)₃ 169. C(CH₃)₃ H —(CH₂)₄—C(CH₃)₃ 170. C₆H₅ H —(CH₂)₄— C(CH₃)₃ 171. C₆H₅ CH₃ —(CH₂)₄— C(CH₃)₃ 172.CF₃ H —(CH₂)₄— C(CH₃)₃ 173. OH F —(CH₂)₄— C(CH₃)₃ 174. OH CN —(CH₂)₄—C(CH₃)₃ 175. N(CH₃)₂ H —(CH₂)₄— C(CH₃)₃ 176. N(CH₃)₂ CH₃ —(CH₂)₄—C(CH₃)₃ 177. OH H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 178. OH CH₃ trans—CH₂—CH═CH—CH₂— C(CH₃)₃ 179. CH₃ H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 180.C(CH₃)₃ H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 181. C₆H₅ H trans—CH₂—CH═CH—CH₂— C(CH₃)₃ 182. C₆H₅ CH₃ trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 183.CF₃ H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 184. OH F trans —CH₂—CH═CH—CH₂—C(CH₃)₃ 185. OH CN trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 186. N(CH₃)₂ H trans—CH₂—CH═CH—CH₂— C(CH₃)₃ 187. N(CH₃)₂ CH₃ trans —CH₂—CH═CH—CH₂— C(CH₃)₃188. OH H trans —CH₂—C(CH₃)═CH—CH₂— C(CH₃)₃ 189. OH CH₃ trans—CH₂—C(CH₃)═CH—CH₂— C(CH₃)₃ 190. CH₃ H trans —CH₂—C(CH₃)═CH—CH₂— C(CH₃)₃191. C(CH₃)₃ H trans —CH₂—C(CH₃)═CH—CH₂— C(CH₃)₃ 192. C₆H₅ H trans—CH₂—C(CH₃)═CH—CH₂— C(CH₃)₃ 193. C₆H₅ CH₃ trans —CH₂—C(CH₃)═CH—CH₂—C(CH₃)₃ 194. CF₃ H trans —CH₂—C(CH₃)═CH—CH₂— C(CH₃)₃ 195. OH F trans—CH₂—C(CH₃)═CH—CH₂— C(CH₃)₃ 196. OH CN trans —CH₂—C(CH₃)═CH—CH₂— C(CH₃)₃197. N(CH₃)₂ H trans —CH₂—C(CH₃)═CH—CH₂— C(CH₃)₃ 198. N(CH₃)₂ CH₃ trans—CH₂—C(CH₃)═CH—CH₂— C(CH₃)₃ 199. OH H —CH₂—CH(CH₃)—CH₂—CH₂— C(CH₃)₃ 200.OH CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— C(CH₃)₃ 201. CH₃ H —CH₂—CH(CH₃)—CH₂—CH₂—C(CH₃)₃ 202. C(CH₃)₃ H —CH₂—CH(CH₃)—CH₂—CH₂— C(CH₃)₃ 203. C₆H₅ H—CH₂—CH(CH₃)—CH₂—CH₂— C(CH₃)₃ 204. C₆H₅ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂—C(CH₃)₃ 205. CF₃ H —CH₂—CH(CH₃)—CH₂—CH₂— C(CH₃)₃ 206. OH F—CH₂—CH(CH₃)—CH₂—CH₂— C(CH₃)₃ 207. OH CN —CH₂—CH(CH₃)—CH₂—CH₂— C(CH₃)₃208. N(CH₃)₂ H —CH₂—CH(CH₃)—CH₂—CH₂— C(CH₃)₃ 209. N(CH₃)₂ CH₃—CH₂—CH(CH₃)—CH₂—CH₂— C(CH₃)₃ 210. OH H —CH₂—CH₂—CH₂—CH(CH₃)— C(CH₃)₃211. OH CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— C(CH₃)₃ 212. CH₃ H—CH₂—CH₂—CH₂—CH(CH₃)— C(CH₃)₃ 213. C(CH₃)₃ H —CH₂—CH₂—CH₂—CH(CH₃)—C(CH₃)₃ 214. C₆H₅ H —CH₂—CH₂—CH₂—CH(CH₃)— C(CH₃)₃ 215. C₆H₅ CH₃—CH₂—CH₂—CH₂—CH(CH₃)— C(CH₃)₃ 216. CF₃ H —CH₂—CH₂—CH₂—CH(CH₃)— C(CH₃)₃217. OH F —CH₂—CH₂—CH₂—CH(CH₃)— C(CH₃)₃ 218. OH CN —CH₂—CH₂—CH₂—CH(CH₃)—C(CH₃)₃ 219. N(CH₃)₂ H —CH₂—CH₂—CH₂—CH(CH₃)— C(CH₃)₃ 220. N(CH₃)₂ CH₃—CH₂—CH₂—CH₂—CH(CH₃)— C(CH₃)₃ 221. OH H —(CH₂)₄— cyclo-C₅H₉ 222. OH CH₃—(CH₂)₄— cyclo-C₅H₉ 223. CH₃ H —(CH₂)₄— cyclo-C₅H₉ 224. C(CH₃)₃ H—(CH₂)₄— cyclo-C₅H₉ 225. C₆H₅ H —(CH₂)₄— cyclo-C₅H₉ 226. C₆H₅ CH₃—(CH₂)₄— cyclo-C₅H₉ 227. CF₃ H —(CH₂)₄— cyclo-C₅H₉ 228. OH F —(CH₂)₄—cyclo-C₅H₉ 229. OH CN —(CH₂)₄— cyclo-C₅H₉ 230. N(CH₃)₂ H —(CH₂)₄—cyclo-C₅H₉ 231. N(CH₃)₂ CH₃ —(CH₂)₄— cyclo-C₅H₉ 232. OH H trans—CH₂—CH═CH—CH₂— cyclo-C₅H₉ 233. OH CH₃ trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉234. CH₃ H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 235. C(CH₃)₃ H trans—CH₂—CH═CH—CH₂— cyclo-C₅H₉ 236. C₆H₅ H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉237. C₆H₅ CH₃ trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 238. CF₃ H trans—CH₂—CH═CH—CH₂— cyclo-C₅H₉ 239. OH F trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉240. OH CN trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 241. N(CH₃)₂ H trans—CH₂—CH═CH—CH₂— cyclo-C₅H₉ 242. N(CH₃)₂ CH₃ trans —CH₂—CH═CH—CH₂—cyclo-C₅H₉ 243. OH H trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₅H₉ 244. OH CH₃trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₅H₉ 245. CH₃ H trans—CH₂—C(CH₃)═CH—CH₂— cyclo-C₅H₉ 246. C(CH₃)₃ H trans —CH₂—C(CH₃)═CH—CH₂—cyclo-C₅H₉ 247. C₆H₅ H trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₅H₉ 248. C₆H₅CH₃ trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₅H₉ 249. CF₃ H trans—CH₂—C(CH₃)═CH—CH₂— cyclo-C₅H₉ 250. OH F trans —CH₂—C(CH₃)═CH—CH₂—cyclo-C₅H₉ 251. OH CN trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₅H₉ 252. N(CH₃)₂H trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₅H₉ 253. N(CH₃)₂ CH₃ trans—CH₂—C(CH₃)═CH—CH₂— cyclo-C₅H₉ 254. OH H —CH₂—CH(CH₃)—CH₂—CH₂—cyclo-C₅H₉ 255. OH CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₅H₉ 256. CH₃ H—CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₅H₉ 257. C(CH₃)₃ H —CH₂—CH(CH₃)—CH₂—CH₂—cyclo-C₅H₉ 258. C₆H₅ H —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₅H₉ 259. C₆H₅ CH₃—CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₅H₉ 260. CF₃ H —CH₂—CH(CH₃)—CH₂—CH₂—cyclo-C₅H₉ 261. OH F —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₅H₉ 262. OH CN—CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₅H₉ 263. N(CH₃)₂ H —CH₂—CH(CH₃)—CH₂—CH₂—cyclo-C₅H₉ 264. N(CH₃)₂ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₅H₉ 265. OH H—CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₅H₉ 266. OH CH₃ —CH₂—CH₂—CH₂—CH(CH₃)—cyclo-C₅H₉ 267. CH₃ H —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₅H₉ 268. C(CH₃)₃ H—CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₅H₉ 269. C₆H₅ H —CH₂—CH₂—CH₂—CH(CH₃)—cyclo-C₅H₉ 270. C₆H₅ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₅H₉ 271. CF₃ H—CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₅H₉ 272. OH F —CH₂—CH₂—CH₂—CH(CH₃)—cyclo-C₅H₉ 273. OH CN —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₅H₉ 274. N(CH₃)₂ H—CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₅H₉ 275. N(CH₃)₂ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)—cyclo-C₅H₉ 276. OH H —(CH₂)₄— CH₃ 277. OH CH₃ —(CH₂)₄— CH₃ 278. CH₃ H—(CH₂)₄— CH₃ 279. C(CH₃)₃ H —(CH₂)₄— CH₃ 280. C₆H₅ H —(CH₂)₄— CH₃ 281.C₆H₅ CH₃ —(CH₂)₄— CH₃ 282. CF₃ H —(CH₂)₄— CH₃ 283. OH F —(CH₂)₄— CH₃284. OH CN —(CH₂)₄— CH₃ 285. N(CH₃)₂ H —(CH₂)₄— CH₃ 286. N(CH₃)₂ CH₃—(CH₂)₄— CH₃ 287. OH H trans —CH₂—CH═CH—CH₂— CH₃ 288. OH CH₃ trans—CH₂—CH═CH—CH₂— CH₃ 289. CH₃ H trans —CH₂—CH═CH—CH₂— CH₃ 290. C(CH₃)₃ Htrans —CH₂—CH═CH—CH₂— CH₃ 291. C₆H₅ H trans —CH₂—CH═CH—CH₂— CH₃ 292.C₆H₅ CH₃ trans —CH₂—CH═CH—CH₂— CH₃ 293. CF₃ H trans —CH₂—CH═CH—CH₂— CH₃294. OH F trans —CH₂—CH═CH—CH₂— CH₃ 295. OH CN trans —CH₂—CH═CH—CH₂— CH₃296. N(CH₃)₂ H trans —CH₂—CH═CH—CH₂— CH₃ 297. N(CH₃)₂ CH₃ trans—CH₂—CH═CH—CH₂— CH₃ 298. OH H trans —CH₂—C(CH₃)═CH—CH₂— CH₃ 299. OH CH₃trans —CH₂—C(CH₃)═CH—CH₂— CH₃ 300. CH₃ H trans —CH₂—C(CH₃)═CH—CH₂— CH₃301. C(CH₃)₃ H trans —CH₂—C(CH₃)═CH—CH₂— CH₃ 302. C₆H₅ H trans—CH₂—C(CH₃)═CH—CH₂— CH₃ 303. C₆H₅ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CH₃ 304.CF₃ H trans —CH₂—C(CH₃)═CH—CH₂— CH₃ 305. OH F trans —CH₂—C(CH₃)═CH—CH₂—CH₃ 306. OH CN trans —CH₂—C(CH₃)═CH—CH₂— CH₃ 307. N(CH₃)₂ H trans—CH₂—C(CH₃)═CH—CH₂— CH₃ 308. N(CH₃)₂ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CH₃309. OH H —CH₂—CH(CH₃)—CH₂—CH₂— CH₃ 310. OH CH₃ —CH₂—CH(CH₃)—CH₂—CH₂—CH₃ 311. CH₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CH₃ 312. C(CH₃)₃ H—CH₂—CH(CH₃)—CH₂—CH₂— CH₃ 313. C₆H₅ H —CH₂—CH(CH₃)—CH₂—CH₂— CH₃ 314.C₆H₅ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— CH₃ 315. CF₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CH₃316. OH F —CH₂—CH(CH₃)—CH₂—CH₂— CH₃ 317. OH CN —CH₂—CH(CH₃)—CH₂—CH₂— CH₃318. N(CH₃)₂ H —CH₂—CH(CH₃)—CH₂—CH₂— CH₃ 319. N(CH₃)₂ CH₃—CH₂—CH(CH₃)—CH₂—CH₂— CH₃ 320. OH H —CH₂—CH₂—CH₂—CH(CH₃)— CH₃ 321. OHCH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CH₃ 322. CH₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CH₃ 323.C(CH₃)₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CH₃ 324. C₆H₅ H —CH₂—CH₂—CH₂—CH(CH₃)—CH₃ 325. C₆H₅ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CH₃ 326. CF₃ H—CH₂—CH₂—CH₂—CH(CH₃)— CH₃ 327. OH F —CH₂—CH₂—CH₂—CH(CH₃)— CH₃ 328. OH CN—CH₂—CH₂—CH₂—CH(CH₃)— CH₃ 329. N(CH₃)₂ H —CH₂—CH₂—CH₂—CH(CH₃)— CH₃ 330.N(CH₃)₂ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CH₃ 331. OH H —(CH₂)₄— CH(CH₃)₂ 332.OH CH₃ —(CH₂)₄— CH(CH₃)₂ 333. CH₃ H —(CH₂)₄— CH(CH₃)₂ 334. C(CH₃)₃ H—(CH₂)₄— CH(CH₃)₂ 335. C₆H₅ H —(CH₂)₄— CH(CH₃)₂ 336. C₆H₅ CH₃ —(CH₂)₄—CH(CH₃)₂ 337. CF₃ H —(CH₂)₄— CH(CH₃)₂ 338. OH F —(CH₂)₄— CH(CH₃)₂ 339.OH CN —(CH₂)₄— CH(CH₃)₂ 340. N(CH₃)₂ H —(CH₂)₄— CH(CH₃)₂ 341. N(CH₃)₂CH₃ —(CH₂)₄— CH(CH₃)₂ 342. OH H trans —CH₂—CH═CH—CH₂— CH(CH₃)₂ 343. OHCH₃ trans —CH₂—CH═CH—CH₂— CH(CH₃)₂ 344. CH₃ H trans —CH₂—CH═CH—CH₂—CH(CH₃)₂ 345. C(CH₃)₃ H trans —CH₂—CH═CH—CH₂— CH(CH₃)₂ 346. C₆H₅ H trans—CH₂—CH═CH—CH₂— CH(CH₃)₂ 347. C₆H₅ CH₃ trans —CH₂—CH═CH—CH₂— CH(CH₃)₂348. CF₃ H trans —CH₂—CH═CH—CH₂— CH(CH₃)₂ 349. OH F trans—CH₂—CH═CH—CH₂— CH(CH₃)₂ 350. OH CN trans —CH₂—CH═CH—CH₂— CH(CH₃)₂ 351.N(CH₃)₂ H trans —CH₂—CH═CH—CH₂— CH(CH₃)₂ 352. N(CH₃)₂ CH₃ trans—CH₂—CH═CH—CH₂— CH(CH₃)₂ 353. OH H trans —CH₂—C(CH₃)═CH—CH₂— CH(CH₃)₂354. OH CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CH(CH₃)₂ 355. CH₃ H trans—CH₂—C(CH₃)═CH—CH₂— CH(CH₃)₂ 356. C(CH₃)₃ H trans —CH₂—C(CH₃)═CH—CH₂—CH(CH₃)₂ 357. C₆H₅ H trans —CH₂—C(CH₃)═CH—CH₂— CH(CH₃)₂ 358. C₆H₅ CH₃trans —CH₂—C(CH₃)═CH—CH₂— CH(CH₃)₂ 359. CF₃ H trans —CH₂—C(CH₃)═CH—CH₂—CH(CH₃)₂ 360. OH F trans —CH₂—C(CH₃)═CH—CH₂— CH(CH₃)₂ 361. OH CN trans—CH₂—C(CH₃)═CH—CH₂— CH(CH₃)₂ 362. N(CH₃)₂ H trans —CH₂—C(CH₃)═CH—CH₂—CH(CH₃)₂ 363. N(CH₃)₂ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CH(CH₃)₂ 364. OH H—CH₂—CH(CH₃)—CH₂—CH₂— CH(CH₃)₂ 365. OH CH₃ —CH₂—CH(CH₃)—CH₂—CH₂—CH(CH₃)₂ 366. CH₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CH(CH₃)₂ 367. C(CH₃)₃ H—CH₂—CH(CH₃)—CH₂—CH₂— CH(CH₃)₂ 368. C₆H₅ H —CH₂—CH(CH₃)—CH₂—CH₂—CH(CH₃)₂ 369. C₆H₅ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— CH(CH₃)₂ 370. CF₃ H—CH₂—CH(CH₃)—CH₂—CH₂— CH(CH₃)₂ 371. OH F —CH₂—CH(CH₃)—CH₂—CH₂— CH(CH₃)₂372. OH CN —CH₂—CH(CH₃)—CH₂—CH₂— CH(CH₃)₂ 373. N(CH₃)₂ H—CH₂—CH(CH₃)—CH₂—CH₂— CH(CH₃)₂ 374. N(CH₃)₂ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂—CH(CH₃)₂ 375. OH H —CH₂—CH₂—CH₂—CH(CH₃)— CH(CH₃)₂ 376. OH CH₃—CH₂—CH₂—CH₂—CH(CH₃)— CH(CH₃)₂ 377. CH₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CH(CH₃)₂378. C(CH₃)₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CH(CH₃)₂ 379. C₆H₅ H—CH₂—CH₂—CH₂—CH(CH₃)— CH(CH₃)₂ 380. C₆H₅ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)—CH(CH₃)₂ 381. CF₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CH(CH₃)₂ 382. OH F—CH₂—CH₂—CH₂—CH(CH₃)— CH(CH₃)₂ 383. OH CN —CH₂—CH₂—CH₂—CH(CH₃)— CH(CH₃)₂384. N(CH₃)₂ H —CH₂—CH₂—CH₂—CH(CH₃)— CH(CH₃)₂ 385. N(CH₃)₂ CH₃—CH₂—CH₂—CH₂—CH(CH₃)— CH(CH₃)₂ 386. OH H —(CH₂)₄— CH₂CH₃ 387. OH CH₃—(CH₂)₄— CH₂CH₃ 388. CH₃ H —(CH₂)₄— CH₂CH₃ 389. C(CH₃)₃ H —(CH₂)₄—CH₂CH₃ 390. C₆H₅ H —(CH₂)₄— CH₂CH₃ 391. C₆H₅ CH₃ —(CH₂)₄— CH₂CH₃ 392.CF₃ H —(CH₂)₄— CH₂CH₃ 393. OH F —(CH₂)₄— CH₂CH₃ 394. OH CN —(CH₂)₄—CH₂CH₃ 395. N(CH₃)₂ H —(CH₂)₄— CH₂CH₃ 396. N(CH₃)₂ CH₃ —(CH₂)₄— CH₂CH₃397. OH H trans —CH₂—CH═CH—CH₂— CH₂CH₃ 398. OH CH₃ trans —CH₂—CH═CH—CH₂—CH₂CH₃ 399. CH₃ H trans —CH₂—CH═CH—CH₂— CH₂CH₃ 400. C(CH₃)₃ H trans—CH₂—CH═CH—CH₂— CH₂CH₃ 401. C₆H₅ H trans —CH₂—CH═CH—CH₂— CH₂CH₃ 402.C₆H₅ CH₃ trans —CH₂—CH═CH—CH₂— CH₂CH₃ 403. CF₃ H trans —CH₂—CH═CH—CH₂—CH₂CH₃ 404. OH F trans —CH₂—CH═CH—CH₂— CH₂CH₃ 405. OH CN trans—CH₂—CH═CH—CH₂— CH₂CH₃ 406. N(CH₃)₂ H trans —CH₂—CH═CH—CH₂— CH₂CH₃ 407.N(CH₃)₂ CH₃ trans —CH₂—CH═CH—CH₂— CH₂CH₃ 408. OH H trans—CH₂—C(CH₃)═CH—CH₂— CH₂CH₃ 409. OH CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₃410. CH₃ H trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₃ 411. C(CH₃)₃ H trans—CH₂—C(CH₃)═CH—CH₂— CH₂CH₃ 412. C₆H₅ H trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₃413. C₆H₅ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₃ 414. CF₃ H trans—CH₂—C(CH₃)═CH—CH₂— CH₂CH₃ 415. OH F trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₃416. OH CN trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₃ 417. N(CH₃)₂ H trans—CH₂—C(CH₃)═CH—CH₂— CH₂CH₃ 418. N(CH₃)₂ CH₃ trans —CH₂—C(CH₃)═CH—CH₂—CH₂CH₃ 419. OH H —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₃ 420. OH CH₃—CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₃ 421. CH₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₃422. C(CH₃)₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₃ 423. C₆H₅ H—CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₃ 424. C₆H₅ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₃425. CF₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₃ 426. OH F —CH₂—CH(CH₃)—CH₂—CH₂—CH₂CH₃ 427. OH CN —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₃ 428. N(CH₃)₂ H—CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₃ 429. N(CH₃)₂ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂—CH₂CH₃ 430. OH H —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₃ 431. OH CH₃—CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₃ 432. CH₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₃433. C(CH₃)₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₃ 434. C₆H₅ H—CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₃ 435. C₆H₅ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₃436. CF₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₃ 437. OH F —CH₂—CH₂—CH₂—CH(CH₃)—CH₂CH₃ 438. OH CN —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₃ 439. N(CH₃)₂ H—CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₃ 440. N(CH₃)₂ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)—CH₂CH₃ 441. OH H —(CH₂)₄— CH₂CH₂CH₃ 442. OH CH₃ —(CH₂)₄— CH₂CH₂CH₃ 443.CH₃ H —(CH₂)₄— CH₂CH₂CH₃ 444. C(CH₃)₃ H —(CH₂)₄— CH₂CH₂CH₃ 445. C₆H₅ H—(CH₂)₄— CH₂CH₂CH₃ 446. C₆H₅ CH₃ —(CH₂)₄— CH₂CH₂CH₃ 447. CF₃ H —(CH₂)₄—CH₂CH₂CH₃ 448. OH F —(CH₂)₄— CH₂CH₂CH₃ 449. OH CN —(CH₂)₄— CH₂CH₂CH₃450. N(CH₃)₂ H —(CH₂)₄— CH₂CH₂CH₃ 451. N(CH₃)₂ CH₃ —(CH₂)₄— CH₂CH₂CH₃452. OH H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 453. OH CH₃ trans—CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 454. CH₃ H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃455. C(CH₃)₃ H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 456. C₆H₅ H trans—CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 457. C₆H₅ CH₃ trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃458. CF₃ H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 459. OH F trans—CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 460. OH CN trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃461. N(CH₃)₂ H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 462. N(CH₃)₂ CH₃ trans—CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 463. OH H trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₂CH₃464. OH CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₂CH₃ 465. CH₃ H trans—CH₂—C(CH₃)═CH—CH₂— CH₂CH₂CH₃ 466. C(CH₃)₃ H trans —CH₂—C(CH₃)═CH—CH₂—CH₂CH₂CH₃ 467. C₆H₅ H trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₂CH₃ 468. C₆H₅ CH₃trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₂CH₃ 469. CF₃ H trans —CH₂—C(CH₃)═CH—CH₂—CH₂CH₂CH₃ 470. OH F trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₂CH₃ 471. OH CN trans—CH₂—C(CH₃)═CH—CH₂— CH₂CH₂CH₃ 472. N(CH₃)₂ H trans —CH₂—C(CH₃)═CH—CH₂—CH₂CH₂CH₃ 473. N(CH₃)₂ CH₃ trans —CH₂—C(CH₃)═CH—CH₂— CH₂CH₂CH₃ 474. OH H—CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₂CH₃ 475. OH CH₃ —CH₂—CH(CH₃)—CH₂—CH₂—CH₂CH₂CH₃ 476. CH₃ H —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₂CH₃ 477. C(CH₃)₃ H—CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₂CH₃ 478. C₆H₅ H —CH₂—CH(CH₃)—CH₂—CH₂—CH₂CH₂CH₃ 479. C₆H₅ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₂CH₃ 480. CF₃ H—CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₂CH₃ 481. OH F —CH₂—CH(CH₃)—CH₂—CH₂—CH₂CH₂CH₃ 482. OH CN —CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₂CH₃ 483. N(CH₃)₂ H—CH₂—CH(CH₃)—CH₂—CH₂— CH₂CH₂CH₃ 484. N(CH₃)₂ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂—CH₂CH₂CH₃ 485. OH H —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₂CH₃ 486. OH CH₃—CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₂CH₃ 487. CH₃ H —CH₂—CH₂—CH₂—CH(CH₃)—CH₂CH₂CH₃ 488. C(CH₃)₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₂CH₃ 489. C₆H₅ H—CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₂CH₃ 490. C₆H₅ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)—CH₂CH₂CH₃ 491. CF₃ H —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₂CH₃ 492. OH F—CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₂CH₃ 493. OH CN —CH₂—CH₂—CH₂—CH(CH₃)—CH₂CH₂CH₃ 494. N(CH₃)₂ H —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₂CH₃ 495. N(CH₃)₂CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— CH₂CH₂CH₃ 496. 1-Methylpyrrol-2-yl H —(CH₂)₄—CF₃ 497. 3-Pyridyl H —(CH₂)₄— CF₃ 498. 3-Thienyl H —(CH₂)₄— CF₃ 499.4-Fluorophenyl H —(CH₂)₄— CF₃ 500. 4-Pyridyl H —(CH₂)₄— CF₃ 501. 3-FurylH —(CH₂)₄— CF₃ 502. 2-Furyl H —(CH₂)₄— CF₃ 503. 2-Pyrrolyl H —(CH₂)₄—CF₃ 504. 2-Thienyl H —(CH₂)₄— CF₃ 505. Pyridazin-2-yl H —(CH₂)₄— CF₃506. 4-Methylthiazol-5-yl H —(CH₂)₄— CF₃ 507. 2-Methyloxazol-4-yl H—(CH₂)₄— CF₃ 508. Cyclopropyl H —(CH₂)₄— CF₃ 509. Cyclobutyl H —(CH₂)₄—CF₃ 510. Cyclopentyl H —(CH₂)₄— CF₃ 511. Cyclohexyl H —(CH₂)₄— CF₃ 512.H₃C—O—CH₂ H —(CH₂)₄— CF₃ 513. Oxan-4-yl H —(CH₂)₄— CF₃ 514.1-Methylpiperidin-4-yl H —(CH₂)₄— CF₃ 515. 1-Methylpyrrol-2-yl H trans—CH₂—CH═CH—CH₂— CF₃ 516. 3-Pyridyl H trans —CH₂—CH═CH—CH₂— CF₃ 517.3-Thienyl H trans —CH₂—CH═CH—CH₂— CF₃ 518. 4-Fluorophenyl H trans—CH₂—CH═CH—CH₂— CF₃ 519. 4-Pyridyl H trans —CH₂—CH═CH—CH₂— CF₃ 520.3-Furyl H trans —CH₂—CH═CH—CH₂— CF₃ 521. 2-Furyl H trans —CH₂—CH═CH—CH₂—CF₃ 522. 2-Pyrrolyl H trans —CH₂—CH═CH—CH₂— CF₃ 523. 2-Thienyl H trans—CH₂—CH═CH—CH₂— CF₃ 524. Pyridazin-2-yl H trans —CH₂—CH═CH—CH₂— CF₃ 525.4-Methylthiazol-5-yl H trans —CH₂—CH═CH—CH₂— CF₃ 526.2-Methyloxazol-4-yl H trans —CH₂—CH═CH—CH₂— CF₃ 527. Cyclopropyl H trans—CH₂—CH═CH—CH₂— CF₃ 528. Cyclobutyl H trans —CH₂—CH═CH—CH₂— CF₃ 529.Cyclopentyl H trans —CH₂—CH═CH—CH₂— CF₃ 530. Cyclohexyl H trans—CH₂—CH═CH—CH₂— CF₃ 531. H₃C—O—CH₂ H trans —CH₂—CH═CH—CH₂— CF₃ 532.Oxan-4-yl H trans —CH₂—CH═CH—CH₂— CF₃ 533. 1-Methylpiperidin-4-yl Htrans —CH₂—CH═CH—CH₂— CF₃ 534. 1-Methylpyrrol-2-yl H —(CH₂)₄— CH₂CH₂CH₃535. 3-Pyridyl H —(CH₂)₄— CH₂CH₂CH₃ 536. 3-Thienyl H —(CH₂)₄— CH₂CH₂CH₃537. 4-Fluorophenyl H —(CH₂)₄— CH₂CH₂CH₃ 538. 4-Pyridyl H —(CH₂)₄—CH₂CH₂CH₃ 539. 3-Furyl H —(CH₂)₄— CH₂CH₂CH₃ 540. 2-Furyl H —(CH₂)₄—CH₂CH₂CH₃ 541. 2-Pyrrolyl H —(CH₂)₄— CH₂CH₂CH₃ 542. 2-Thienyl H —(CH₂)₄—CH₂CH₂CH₃ 543. Pyridazin-2-yl H —(CH₂)₄— CH₂CH₂CH₃ 544.4-Methylthiazol-5-yl H —(CH₂)₄— CH₂CH₂CH₃ 545. 2-Methyloxazol-4-yl H—(CH₂)₄— CH₂CH₂CH₃ 546. Cyclopropyl H —(CH₂)₄— CH₂CH₂CH₃ 547. CyclobutylH —(CH₂)₄— CH₂CH₂CH₃ 548. Cyclopentyl H —(CH₂)₄— CH₂CH₂CH₃ 549.Cyclohexyl H —(CH₂)₄— CH₂CH₂CH₃ 550. H₃C—O—CH₂ H —(CH₂)₄— CH₂CH₂CH₃ 551.Oxan-4-yl H —(CH₂)₄— CH₂CH₂CH₃ 552. 1-Methylpiperidin-4-yl H —(CH₂)₄—CH₂CH₂CH₃ 553. 1-Methylpyrrol-2-yl H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃554. 3-Pyridyl H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 555. 3-Thienyl H trans—CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 556. 4-Fluorophenyl H trans —CH₂—CH═CH—CH₂—CH₂CH₂CH₃ 557. 4-Pyridyl H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 558. 3-FurylH trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 559. 2-Furyl H trans —CH₂—CH═CH—CH₂—CH₂CH₂CH₃ 560. 2-Pyrrolyl H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 561.2-Thienyl H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 562. Pyridazin-2-yl H trans—CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 563. 4-Methylthiazol-5-yl H trans—CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 564. 2-Methyloxazol-4-yl H trans—CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 565. Cyclopropyl H trans —CH₂—CH═CH—CH₂—CH₂CH₂CH₃ 566. Cyclobutyl H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 567.Cyclopentyl H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 568. Cyclohexyl H trans—CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 569. H₃C—O—CH₂ H trans —CH₂—CH═CH—CH₂—CH₂CH₂CH₃ 570. Oxan-4-yl H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 571.1-Methylpiperidin-4-yl H trans —CH₂—CH═CH—CH₂— CH₂CH₂CH₃ 572.1-Methylpyrrol-2-yl H —(CH₂)₄— CH₃ 573. 3-Pyridyl H —(CH₂)₄— CH₃ 574.3-Thienyl H —(CH₂)₄— CH₃ 575. 4-Fluorophenyl H —(CH₂)₄— CH₃ 576.4-Pyridyl H —(CH₂)₄— CH₃ 577. 3-Furyl H —(CH₂)₄— CH₃ 578. 2-Furyl H—(CH₂)₄— CH₃ 579. 2-Pyrrolyl H —(CH₂)₄— CH₃ 580. 2-Thienyl H —(CH₂)₄—CH₃ 581. Pyridazin-2-yl H —(CH₂)₄— CH₃ 582. 4-Methylthiazol-5-yl H—(CH₂)₄— CH₃ 583. 2-Methyloxazol-4-yl H —(CH₂)₄— CH₃ 584. Cyclopropyl H—(CH₂)₄— CH₃ 585. Cyclobutyl H —(CH₂)₄— CH₃ 586. Cyclopentyl H —(CH₂)₄—CH₃ 587. Cyclohexyl H —(CH₂)₄— CH₃ 588. H₃C—O—CH₂ H —(CH₂)₄— CH₃ 589.Oxan-4-yl H —(CH₂)₄— CH₃ 590. 1-Methylpiperidin-4-yl H —(CH₂)₄— CH₃ 591.1-Methylpyrrol-2-yl H trans —CH₂—CH═CH—CH₂— CH₃ 592. 3-Pyridyl H trans—CH₂—CH═CH—CH₂— CH₃ 593. 3-Thienyl H trans —CH₂—CH═CH—CH₂— CH₃ 594.4-Fluorophenyl H trans —CH₂—CH═CH—CH₂— CH₃ 595. 4-Pyridyl H trans—CH₂—CH═CH—CH₂— CH₃ 596. 3-Furyl H trans —CH₂—CH═CH—CH₂— CH₃ 597.2-Furyl H trans —CH₂—CH═CH—CH₂— CH₃ 598. 2-Pyrrolyl H trans—CH₂—CH═CH—CH₂— CH₃ 599. 2-Thienyl H trans —CH₂—CH═CH—CH₂— CH₃ 600.Pyridazin-2-yl H trans —CH₂—CH═CH—CH₂— CH₃ 601. 4-Methylthiazol-5-yl Htrans —CH₂—CH═CH—CH₂— CH₃ 602. 2-Methyloxazol-4-yl H trans—CH₂—CH═CH—CH₂— CH₃ 603. Cyclopropyl H trans —CH₂—CH═CH—CH₂— CH₃ 604.Cyclobutyl H trans —CH₂—CH═CH—CH₂— CH₃ 605. Cyclopentyl H trans—CH₂—CH═CH—CH₂— CH₃ 606. Cyclohexyl H trans —CH₂—CH═CH—CH₂— CH₃ 607.H₃C—O—CH₂ H trans —CH₂—CH═CH—CH₂— CH₃ 608. Oxan-4-yl H trans—CH₂—CH═CH—CH₂— CH₃ 609. 1-Methylpiperidin-4-yl H trans —CH₂—CH═CH—CH₂—CH₃ 610. 1-Methylpyrrol-2-yl H —(CH₂)₄— C(CH₃)₃ 611. 3-Pyridyl H—(CH₂)₄— C(CH₃)₃ 612. 3-Thienyl H —(CH₂)₄— C(CH₃)₃ 613. 4-Fluorophenyl H—(CH₂)₄— C(CH₃)₃ 614. 4-Pyridyl H —(CH₂)₄— C(CH₃)₃ 615. 3-Furyl H—(CH₂)₄— C(CH₃)₃ 616. 2-Furyl H —(CH₂)₄— C(CH₃)₃ 617. 2-Pyrrolyl H—(CH₂)₄— C(CH₃)₃ 618. 2-Thienyl H —(CH₂)₄— C(CH₃)₃ 619. Pyridazin-2-yl H—(CH₂)₄— C(CH₃)₃ 620. 4-Methylthiazol-5-yl H —(CH₂)₄— C(CH₃)₃ 621.2-Methyloxazol-4-yl H —(CH₂)₄— C(CH₃)₃ 622. Cyclopropyl H —(CH₂)₄—C(CH₃)₃ 623. Cyclobutyl H —(CH₂)₄— C(CH₃)₃ 624. Cyclopentyl H —(CH₂)₄—C(CH₃)₃ 625. Cyclohexyl H —(CH₂)₄— C(CH₃)₃ 626. H₃C—O—CH₂ H —(CH₂)₄—C(CH₃)₃ 627. Oxan-4-yl H —(CH₂)₄— C(CH₃)₃ 628. 1-Methylpiperidin-4-yl H—(CH₂)₄— C(CH₃)₃ 629. 1-Methylpyrrol-2-yl H trans —CH₂—CH═CH—CH₂—C(CH₃)₃ 630. 3-Pyridyl H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 631. 3-Thienyl Htrans —CH₂—CH═CH—CH₂— C(CH₃)₃ 632. 4-Fluorophenyl H trans—CH₂—CH═CH—CH₂— C(CH₃)₃ 633. 4-Pyridyl H trans —CH₂—CH═CH—CH₂— C(CH₃)₃634. 3-Furyl H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 635. 2-Furyl H trans—CH₂—CH═CH—CH₂— C(CH₃)₃ 636. 2-Pyrrolyl H trans —CH₂—CH═CH—CH₂— C(CH₃)₃637. 2-Thienyl H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 638. Pyridazin-2-yl Htrans —CH₂—CH═CH—CH₂— C(CH₃)₃ 639. 4-Methylthiazol-5-yl H trans—CH₂—CH═CH—CH₂— C(CH₃)₃ 640. 2-Methyloxazol-4-yl H trans —CH₂—CH═CH—CH₂—C(CH₃)₃ 641. Cyclopropyl H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 642. CyclobutylH trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 643. Cyclopentyl H trans —CH₂—CH═CH—CH₂—C(CH₃)₃ 644. Cyclohexyl H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 645. H₃C—O—CH₂ Htrans —CH₂—CH═CH—CH₂— C(CH₃)₃ 646. Oxan-4-yl H trans —CH₂—CH═CH—CH₂—C(CH₃)₃ 647. 1-Methylpiperidin-4-yl H trans —CH₂—CH═CH—CH₂— C(CH₃)₃ 648.1-Methylpyrrol-2-yl H —(CH₂)₄— cyclo-C₅H₉ 649. 3-Pyridyl H —(CH₂)₄—cyclo-C₅H₉ 650. 3-Thienyl H —(CH₂)₄— cyclo-C₅H₉ 651. 4-Fluorophenyl H—(CH₂)₄— cyclo-C₅H₉ 652. 4-Pyridyl H —(CH₂)₄— cyclo-C₅H₉ 653. 3-Furyl H—(CH₂)₄— cyclo-C₅H₉ 654. 2-Furyl H —(CH₂)₄— cyclo-C₅H₉ 655. 2-Pyrrolyl H—(CH₂)₄— cyclo-C₅H₉ 656. 2-Thienyl H —(CH₂)₄— cyclo-C₅H₉ 657.Pyridazin-2-yl H —(CH₂)₄— cyclo-C₅H₉ 658. 4-Methylthiazol-5-yl H—(CH₂)₄— cyclo-C₅H₉ 659. 2-Methyloxazol-4-yl H —(CH₂)₄— cyclo-C₅H₉ 660.Cyclopropyl H —(CH₂)₄— cyclo-C₅H₉ 661. Cyclobutyl H —(CH₂)₄— cyclo-C₅H₉662. Cyclopentyl H —(CH₂)₄— cyclo-C₅H₉ 663. Cyclohexyl H —(CH₂)₄—cyclo-C₅H₉ 664. H₃C—O—CH₂ H —(CH₂)₄— cyclo-C₅H₉ 665. Oxan-4-yl H—(CH₂)₄— cyclo-C₅H₉ 666. 1-Methylpiperidin-4-yl H —(CH₂)₄— cyclo-C₅H₉667. 1-Methylpyrrol-2-yl H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 668.3-Pyridyl H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 669. 3-Thienyl H trans—CH₂—CH═CH—CH₂— cyclo-C₅H₉ 670. 4-Fluorophenyl H trans —CH₂—CH═CH—CH₂—cyclo-C₅H₉ 671. 4-Pyridyl H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 672.3-Furyl H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 673. 2-Furyl H trans—CH₂—CH═CH—CH₂— cyclo-C₅H₉ 674. 2-Pyrrolyl H trans —CH₂—CH═CH—CH₂—cyclo-C₅H₉ 675. 2-Thienyl H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 676.Pyridazin-2-yl H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 677.4-Methylthiazol-5-yl H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 678.2-Methyloxazol-4-yl H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 679. CyclopropylH trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 680. Cyclobutyl H trans—CH₂—CH═CH—CH₂— cyclo-C₅H₉ 681. Cyclopentyl H trans —CH₂—CH═CH—CH₂—cyclo-C₅H₉ 682. Cyclohexyl H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 683.H₃C—O—CH₂ H trans —CH₂—CH═CH—CH₂— cyclo-C₅H₉ 684. Oxan-4-yl H trans—CH₂—CH═CH—CH₂— cyclo-C₅H₉ 685. 1-Methylpiperidin-4-yl H trans—CH₂—CH═CH—CH₂— cyclo-C₅H₉ 686. OH H —(CH₂)₄— cyclo-C₃H₅ 687. OH CH₃—(CH₂)₄— cyclo-C₃H₅ 688. CH₃ H —(CH₂)₄— cyclo-C₃H₅ 689. C(CH₃)₃ H—(CH₂)₄— cyclo-C₃H₅ 690. C₆H₅ H —(CH₂)₄— cyclo-C₃H₅ 691. C₆H₅ CH₃—(CH₂)₄— cyclo-C₃H₅ 692. CF₃ H —(CH₂)₄— cyclo-C₃H₅ 693. OH F —(CH₂)₄—cyclo-C₃H₅ 694. OH CN —(CH₂)₄— cyclo-C₃H₅ 695. N(CH₃)₂ H —(CH₂)₄—cyclo-C₃H₅ 696. N(CH₃)₂ CH₃ —(CH₂)₄— cyclo-C₃H₅ 697. OH H trans—CH₂—CH═CH—CH₂— cyclo-C₃H₅ 698. OH CH₃ trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅699. CH₃ H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 700. C(CH₃)₃ H trans—CH₂—CH═CH—CH₂— cyclo-C₃H₅ 701. C₆H₅ H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅702. C₆H₅ CH₃ trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 703. CF₃ H trans—CH₂—CH═CH—CH₂— cyclo-C₃H₅ 704. OH F trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅705. OH CN trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 706. N(CH₃)₂ H trans—CH₂—CH═CH—CH₂— cyclo-C₃H₅ 707. N(CH₃)₂ CH₃ trans —CH₂—CH═CH—CH₂—cyclo-C₃H₅ 708. OH H trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₃H₅ 709. OH CH₃trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₃H₅ 710. CH₃ H trans—CH₂—C(CH₃)═CH—CH₂— cyclo-C₃H₅ 711. C(CH₃)₃ H trans —CH₂—C(CH₃)═CH—CH₂—cyclo-C₃H₅ 712. C₆H₅ H trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₃H₅ 713. C₆H₅CH₃ trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₃H₅ 714. CF₃ H trans—CH₂—C(CH₃)═CH—CH₂— cyclo-C₃H₅ 715. OH F trans —CH₂—C(CH₃)═CH—CH₂—cyclo-C₃H₅ 716. OH CN trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₃H₅ 717. N(CH₃)₂H trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₃H₅ 718. N(CH₃)₂ CH₃ trans—CH₂—C(CH₃)═CH—CH₂— cyclo-C₃H₅ 719. OH H —CH₂—CH(CH₃)—CH₂—CH₂—cyclo-C₃H₅ 720. OH CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₃H₅ 721. CH₃ H—CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₃H₅ 722. C(CH₃)₃ H —CH₂—CH(CH₃)—CH₂—CH₂—cyclo-C₃H₅ 723. C₆H₅ H —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₃H₅ 724. C₆H₅ CH₃—CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₃H₅ 725. CF₃ H —CH₂—CH(CH₃)—CH₂—CH₂—cyclo-C₃H₅ 726. OH F —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₃H₅ 727. OH CN—CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₃H₅ 728. N(CH₃)₂ H —CH₂—CH(CH₃)—CH₂—CH₂—cyclo-C₃H₅ 729. N(CH₃)₂ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₃H₅ 730. OH H—CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₃H₅ 731. OH CH₃ —CH₂—CH₂—CH₂—CH(CH₃)—cyclo-C₃H₅ 732. CH₃ H —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₃H₅ 733. C(CH₃)₃ H—CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₃H₅ 734. C₆H₅ H —CH₂—CH₂—CH₂—CH(CH₃)—cyclo-C₃H₅ 735. C₆H₅ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₃H₅ 736. CF₃ H—CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₃H₅ 737. OH F —CH₂—CH₂—CH₂—CH(CH₃)—cyclo-C₃H₅ 738. OH CN —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₃H₅ 739. N(CH₃)₂ H—CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₃H₅ 740. N(CH₃)₂ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)—cyclo-C₃H₅ 741. 1-Methylpyrrol-2-yl H —(CH₂)₄— cyclo-C₃H₅ 742. 3-PyridylH —(CH₂)₄— cyclo-C₃H₅ 743. 3-Thienyl H —(CH₂)₄— cyclo-C₃H₅ 744.4-Fluorophenyl H —(CH₂)₄— cyclo-C₃H₅ 745. 4-Pyridyl H —(CH₂)₄—cyclo-C₃H₅ 746. 3-Furyl H —(CH₂)₄— cyclo-C₃H₅ 747. 2-Furyl H —(CH₂)₄—cyclo-C₃H₅ 748. 2-Pyrrolyl H —(CH₂)₄— cyclo-C₃H₅ 749. 2-Thienyl H—(CH₂)₄— cyclo-C₃H₅ 750. Pyridazin-2-yl H —(CH₂)₄— cyclo-C₃H₅ 751.4-Methylthiazol-5-yl H —(CH₂)₄— cyclo-C₃H₅ 752. 2-Methyloxazol-4-yl H—(CH₂)₄— cyclo-C₃H₅ 753. Cyclopropyl H —(CH₂)₄— cyclo-C₃H₅ 754.Cyclobutyl H —(CH₂)₄— cyclo-C₃H₅ 755. Cyclopentyl H —(CH₂)₄— cyclo-C₃H₅756. Cyclohexyl H —(CH₂)₄— cyclo-C₃H₅ 757. H₃C—O—CH₂ H —(CH₂)₄—cyclo-C₃H₅ 758. Oxan-4-yl H —(CH₂)₄— cyclo-C₃H₅ 759.1-Methylpiperidin-4-yl H —(CH₂)₄— cyclo-C₃H₅ 760. 1-Methylpyrrol-2-yl Htrans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 761. 3-Pyridyl H trans —CH₂—CH═CH—CH₂—cyclo-C₃H₅ 762. 3-Thienyl H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 763.4-Fluorophenyl H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 764. 4-Pyridyl H trans—CH₂—CH═CH—CH₂— cyclo-C₃H₅ 765. 3-Furyl H trans —CH₂—CH═CH—CH₂—cyclo-C₃H₅ 766. 2-Furyl H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 767.2-Pyrrolyl H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 768. 2-Thienyl H trans—CH₂—CH═CH—CH₂— cyclo-C₃H₅ 769. Pyridazin-2-yl H trans —CH₂—CH═CH—CH₂—cyclo-C₃H₅ 770. 4-Methylthiazol-5-yl H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅771. 2-Methyloxazol-4-yl H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 772.Cyclopropyl H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 773. Cyclobutyl H trans—CH₂—CH═CH—CH₂— cyclo-C₃H₅ 774. Cyclopentyl H trans —CH₂—CH═CH—CH₂—cyclo-C₃H₅ 775. Cyclohexyl H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 776.H₃C—O—CH₂ H trans —CH₂—CH═CH—CH₂— cyclo-C₃H₅ 777. Oxan-4-yl H trans—CH₂—CH═CH—CH₂— cyclo-C₃H₅ 778. 1-Methylpiperidin-4-yl H trans—CH₂—CH═CH—CH₂— cyclo-C₃H₅ 779. OH H —(CH₂)₄— cyclo-C₄H₇ 780. OH CH₃—(CH₂)₄— cyclo-C₄H₇ 781. CH₃ H —(CH₂)₄— cyclo-C₄H₇ 782. C(CH₃)₃ H—(CH₂)₄— cyclo-C₄H₇ 783. C₆H₅ H —(CH₂)₄— cyclo-C₄H₇ 784. C₆H₅ CH₃—(CH₂)₄— cyclo-C₄H₇ 785. CF₃ H —(CH₂)₄— cyclo-C₄H₇ 786. OH F —(CH₂)₄—cyclo-C₄H₇ 787. OH CN —(CH₂)₄— cyclo-C₄H₇ 788. N(CH₃)₂ H —(CH₂)₄—cyclo-C₄H₇ 789. N(CH₃)₂ CH₃ —(CH₂)₄— cyclo-C₄H₇ 790. OH H trans—CH₂—CH═CH—CH₂— cyclo-C₄H₇ 791. OH CH₃ trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇792. CH₃ H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 793. C(CH₃)₃ H trans—CH₂—CH═CH—CH₂— cyclo-C₄H₇ 794. C₆H₅ H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇795. C₆H₅ CH₃ trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 796. CF₃ H trans—CH₂—CH═CH—CH₂— cyclo-C₄H₇ 797. OH F trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇798. OH CN trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 799. N(CH₃)₂ H trans—CH₂—CH═CH—CH₂— cyclo-C₄H₇ 800. N(CH₃)₂ CH₃ trans —CH₂—CH═CH—CH₂—cyclo-C₄H₇ 801. OH H trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₄H₇ 802. OH CH₃trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₄H₇ 803. CH₃ H trans—CH₂—C(CH₃)═CH—CH₂— cyclo-C₄H₇ 804. C(CH₃)₃ H trans —CH₂—C(CH₃)═CH—CH₂—cyclo-C₄H₇ 805. C₆H₅ H trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₄H₇ 806. C₆H₅CH₃ trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₄H₇ 807. CF₃ H trans—CH₂—C(CH₃)═CH—CH₂— cyclo-C₄H₇ 808. OH F trans —CH₂—C(CH₃)═CH—CH₂—cyclo-C₄H₇ 809. OH CN trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₄H₇ 810. N(CH₃)₂H trans —CH₂—C(CH₃)═CH—CH₂— cyclo-C₄H₇ 811. N(CH₃)₂ CH₃ trans—CH₂—C(CH₃)═CH—CH₂— cyclo-C₄H₇ 812. OH H —CH₂—CH(CH₃)—CH₂—CH₂—cyclo-C₄H₇ 813. OH CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₄H₇ 814. CH₃ H—CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₄H₇ 815. C(CH₃)₃ H —CH₂—CH(CH₃)—CH₂—CH₂—cyclo-C₄H₇ 816. C₆H₅ H —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₄H₇ 817. C₆H₅ CH₃—CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₄H₇ 818. CF₃ H —CH₂—CH(CH₃)—CH₂—CH₂—cyclo-C₄H₇ 819. OH F —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₄H₇ 820. OH CN—CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₄H₇ 821. N(CH₃)₂ H —CH₂—CH(CH₃)—CH₂—CH₂—cyclo-C₄H₇ 822. N(CH₃)₂ CH₃ —CH₂—CH(CH₃)—CH₂—CH₂— cyclo-C₄H₇ 823. OH H—CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₄H₇ 824. OH CH₃ —CH₂—CH₂—CH₂—CH(CH₃)—cyclo-C₄H₇ 825. CH₃ H —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₄H₇ 826. C(CH₃)₃ H—CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₄H₇ 827. C₆H₅ H —CH₂—CH₂—CH₂—CH(CH₃)—cyclo-C₄H₇ 828. C₆H₅ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₄H₇ 829. CF₃ H—CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₄H₇ 830. OH F —CH₂—CH₂—CH₂—CH(CH₃)—cyclo-C₄H₇ 831. OH CN —CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₄H₇ 832. N(CH₃)₂ H—CH₂—CH₂—CH₂—CH(CH₃)— cyclo-C₄H₇ 833. N(CH₃)₂ CH₃ —CH₂—CH₂—CH₂—CH(CH₃)—cyclo-C₄H₇ 834. 1-Methylpyrrol-2-yl H —(CH₂)₄— cyclo-C₄H₇ 835. 3-PyridylH —(CH₂)₄— cyclo-C₄H₇ 836. 3-Thienyl H —(CH₂)₄— cyclo-C₄H₇ 837.4-Fluorophenyl H —(CH₂)₄— cyclo-C₄H₇ 838. 4-Pyridyl H —(CH₂)₄—cyclo-C₄H₇ 839. 3-Furyl H —(CH₂)₄— cyclo-C₄H₇ 840. 2-Furyl H —(CH₂)₄—cyclo-C₄H₇ 841. 2-Pyrrolyl H —(CH₂)₄— cyclo-C₄H₇ 842. 2-Thienyl H—(CH₂)₄— cyclo-C₄H₇ 843. Pyridazin-2-yl H —(CH₂)₄— cyclo-C₄H₇ 844.4-Methylthiazol-5-yl H —(CH₂)₄— cyclo-C₄H₇ 845. 2-Methyloxazol-4-yl H—(CH₂)₄— cyclo-C₄H₇ 846. Cyclopropyl H —(CH₂)₄— cyclo-C₄H₇ 847.Cyclobutyl H —(CH₂)₄— cyclo-C₄H₇ 848. Cyclopentyl H —(CH₂)₄— cyclo-C₄H₇849. Cyclohexyl H —(CH₂)₄— cyclo-C₄H₇ 850. H₃C—O—CH₂ H —(CH₂)₄—cyclo-C₄H₇ 851. Oxan-4-yl H —(CH₂)₄— cyclo-C₄H₇ 852.1-Methylpiperidin-4-yl H —(CH₂)₄— cyclo-C₄H₇ 853. 1-Methylpyrrol-2-yl Htrans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 854. 3-Pyridyl H trans —CH₂—CH═CH—CH₂—cyclo-C₄H₇ 855. 3-Thienyl H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 856.4-Fluorophenyl H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 857. 4-Pyridyl H trans—CH₂—CH═CH—CH₂— cyclo-C₄H₇ 858. 3-Furyl H trans —CH₂—CH═CH—CH₂—cyclo-C₄H₇ 859. 2-Furyl H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 860.2-Pyrrolyl H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 861. 2-Thienyl H trans—CH₂—CH═CH—CH₂— cyclo-C₄H₇ 862. Pyridazin-2-yl H trans —CH₂—CH═CH—CH₂—cyclo-C₄H₇ 863. 4-Methylthiazol-5-yl H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇864. 2-Methyloxazol-4-yl H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 865.Cyclopropyl H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 866. Cyclobutyl H trans—CH₂—CH═CH—CH₂— cyclo-C₄H₇ 867. Cyclopentyl H trans —CH₂—CH═CH—CH₂—cyclo-C₄H₇ 868. Cyclohexyl H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 869.H₃C—O—CH₂ H trans —CH₂—CH═CH—CH₂— cyclo-C₄H₇ 870. Oxan-4-yl H trans—CH₂—CH═CH—CH₂— cyclo-C₄H₇ 871. 1-Methylpiperidin-4-yl H trans—CH₂—CH═CH—CH₂— cyclo-C₄H₇

Examples of further compounds of the general formula I.1 are thecompounds of the general formula I.1b,

in which A′, R^(a), R¹ and R² have the meanings indicated above, inparticular the meanings indicated as preferred. Examples of suchcompounds are the compounds I.1b.1 to I.1b.871 where the variables A′,R^(a), R¹ and R² in each case jointly have the meaning indicated in oneof lines 1 to 647 of Table 1.

Examples of further compounds of the general formula I.1 are thecompounds of the general formula I.1c,

in which A′, R^(a), R¹ and R² have the meanings indicated above, inparticular the meanings indicated as preferred. Examples of suchcompounds are the compounds I.1c.1 to I.1c.871 where the variables A′,R^(a), R¹ and R² in each case jointly have the meaning indicated in oneof lines 1 to 871 of Table 1.

Examples of further compounds of the general formula I.1 are thecompounds of the general formula I.1d,

in which A′, R^(a), R¹ and R² have the meanings indicated above, inparticular the meanings indicated as preferred. Examples of suchcompounds are the compounds I.1d.1 to I.1d.871 where the variables A′,R^(a), R¹ and R² in each case jointly have the meaning indicated in oneof lines 1 to 871 of Table 1.

Examples of further compounds of the general formula I.1 are thecompounds of the general formula I.1e,

in which A′, R^(a), R¹ and R² have the meanings indicated above, inparticular the meanings indicated as preferred. Examples of suchcompounds are the compounds I.1e.1 to I.1e.871 where the variables A′,R^(a), R¹ and R² in each case jointly have the meaning indicated in oneof lines 1 to 871 of Table 1.

Examples of further compounds of the general formula I.1 are thecompounds of the general formula I.1f,

in which A′, R^(a), R¹ and R² have the meanings indicated above, inparticular the meanings indicated as preferred. Examples of suchcompounds are the compounds I.1f.1 to I.1f.871 where the variables A′,R^(a), R¹ and R² in each case jointly have the meaning indicated in oneof lines 1 to 871 of Table 1.

Preparation of the compounds of the invention takes place in analogy tomethods known from the literature. An important approach to thecompounds of the invention is depicted in Scheme 1.

In Scheme 1, R¹, R², A, X, Y and Ar have the aforementioned meanings. L₁and L₂ are leaving groups which can be displaced nucleophilically.Examples of suitable leaving groups which can be displacednucleophilically are halogen, especially chlorine, bromine or iodine,alkyl- and arylsulfonate such as mesylate, tosylate. L₁ and L₂ arepreferably different from one another and differ in reactivity. Forexample, L₁ is bromine or iodine and L₂ is chlorine. The reactionconditions necessary for the reaction correspond to the reactionconditions usual for nucleophilic substitutions.

Compounds of the general formula IV are either known from theliterature, e.g. disclosed in WO 96/02519, WO 97/25324, WO 99/02503 orthe literature cited in these publications, or can be prepared by theprocesses described therein.

The pyrimidinone compounds of the formulae II are known and in somecases commercially available or can be prepared by known processes forpyrimidinone synthesis as described, for example, in Austr. J. Chem.1968, 221, pp. 243-255; J. Med. Chem. 1978, 21, pp. 623-628; TetrahedronLett. 1986, 27, pp. 2611-2612; Chemiker Ztg. 1977, 6, p. 305. Thecompounds II can also be prepared by the methods indicated in Scheme 4.

It is additionally possible for compounds of the formula II, where R¹ isoptionally substituted alkenyl, optionally substituted phenyl oroptionally substituted C-bonded heteroaryl, to be prepared by Suzukicoupling via the route shown in Scheme 2.

In Scheme 2, R¹ is optionally substituted alkenyl, optionallysubstituted phenyl or optionally substituted C-bonded heteroaryl. X is agroup B(OH)₂, B(OR)₂ or the radical (BO)₃/3 derived from thecorresponding boronic anhydride. “Pd” is a palladium(0) complex whichpreferably has 4 trialkylphosphine or triarylphosphine ligands. R² hasthe meanings indicated above and is in particular hydrogen orC₁-C₄-alkyl.

Coupling of V with the compound R^(1′)—X takes place under theconditions of a Suzuki coupling (for review, see A. Suzuki et al. inChem. Rev. 1995, 95, pp. 2457-2483). The reaction conditions necessaryfor Suzuki coupling of 2,4-dichloropyrimidines V with R^(1′)—X are knownfrom the literature, e.g. from J. Org. Chem. 66(21) (2001), pp.7124-7128. The 2-chloropyrimidine VI obtained in this case can beconverted into the corresponding 2-pyrimidinone II in a manner known perse, e.g. under the conditions indicated in Acta Chem. Scand. B, 1984,38, pp. 505-508.

A further possibility for preparing the compounds of the formula II inwhich R¹ is optionally substituted C₁-C₆-alkyl or C₃-C₆-cycloalkyl, inparticular ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, and R²is H, is for example by the process shown in Scheme 3.

In Scheme 3, R is, for example, C₁-C₄-alkyl. In Scheme 3 there isinitial conversion of a ketone VII with a formic ester VIII, e.g. methylformate, in a manner known per se into the ketal IX (see Helv. Chim.Acta 2002, 85, 2926-2929, Ex. 6). The reaction is normally carried outin the presence of a base such as an alcoholate in an inert solvent suchas an ether. Reaction of the resulting ketal IX with urea X to form thecorresponding 2-pyrimidinone II takes place under conditions known fromthe literature, e.g. as described in Aust. J. Chem. 1968, 21, 243-55 (inparticular page 252).

The 2-pyrimidinones II in which R¹ is hydrogen and R² is optionallysubstituted phenyl can be prepared for example by the process shown inScheme 4.

In Scheme 4, Hal is halogen, in particular bromine or chlorine. Couplingof the halopyrimidinone XI with the borate XII takes place under Suzukiconditions (see Tetrahedron 1997, 53, 14437-50). The modified Suzukicross-coupling between the pyridinone XI and the borate XII normallytakes place in aqueous solvents in the presence of a phosphine-free Pdcatalyst such as palladium(II) chloride and in the presence of a base.Examples of suitable bases are alkali metal hydroxides such as sodiumhydroxide. The pyridinones XI and the borates XII are known from theliterature.

The pyrimidinone compounds I of the invention, in which R¹ is SH, can beprepared for example by the process shown in Scheme 5.

In Scheme 5, R^(a) and R^(b) are for example both C₁-C₄-alkyl or formwith the nitrogen atom to which they are bonded a saturated ring, e.g. apiperidinyl, piperazinyl, pyrrolidinyl or morpholinyl radical. R is, forexample, C₁-C₄-alkyl. The reaction shown in Scheme 5 is known inprinciple, for example from J. Hetercycl. Chem. 5 (1968) pp. 837-844 orfrom WO 00/61579, and can be employed in an analogous manner forpreparing the compounds I of the invention. The same applies to thestarting compounds XIII. The compounds of the formula XIV are known forexample from the prior art cited at the outset or can be prepared in amanner known per se from the corresponding halogen compound Ar—B-A-Halin which Hal is chlorine, bromine or iodine. For example, the amine XIVAr—B-A-Hal can be prepared by conversion into the corresponding azideAr—B-A-N₃ and subsequent reduction to the amine. The conditionsnecessary for this are known to the skilled worker, e.g. from Chem. Rev.1994, 94, p. 1, and can be applied analogously to the preparation ofXIV. The halogen compounds Ar—B-A-Hal are disclosed for example in WO96/02519, WO 97/25324, WO 99/09015, WO 99/02503 or can be prepared inanalogy to the processes described therein.

The thiol group in compounds I with R¹═SH can be converted into otherradicals R¹ by standard processes of organic chemistry. An overview isgiven in Scheme 6.

Processes for this purpose are known to the skilled worker and includeconversion of SH into SR⁶ by alkylation, oxidation of SR⁶ to thecorresponding SOR⁶ and SO₂R⁶ groups, oxidative degradation of SH to OHwith, where appropriate, subsequent alkylation or esterification to givethe groups OR^(3a), OC(O)NR⁴R⁵ or OC(O)R⁸.

The pyrimidinone compounds I.1 of the invention, in which R¹ is NR⁴R⁵,can be prepared for example by the process shown in Scheme 7.

In Scheme 7, B and Ar have the aforementioned meanings. As shown inScheme 7, initially compound I in which R¹ is OH is converted into thecorresponding thiol I with R¹═SH. Examples of suitable sulfurizingagents are organophosphorus sulfides such as Lawesson's reagent,organotin sulfides or phosphorus(V) sulfide. A preferred sulfurizingagent is phosphorus pentasulfide (P₄S₁₀). The conditions necessary forthe thionation are known to the skilled worker, e.g. from J. Med. Chem.1984, 27, 1470-80 (in particular page 1478, Example 8b). The thiol Iwith R¹═SH which is obtained in this way can then be converted byreaction with a compound of the formula HNR⁴R⁵ in which R⁴ and R⁵ havethe aforementioned meanings into other compounds I with R¹═NR⁴R⁵. Thereaction usually takes place in an inert solvent. The activation energynecessary for the reaction can be introduced into the reaction mixtureby means of microwaves (for reaction with use of microwaves, seeTetrahedron 2001, 57, pp. 9199 et seq., pp. 9225 et seq. and in general“Microwaves in Organic Synthesis”, André Loupy (Editor), Wiley-VCH2002).

The pyrimidinone compounds II in which R¹ is NR⁴R⁵ can be prepared forexample in analogy to above Scheme 7. The preparation is outlined inScheme 8.

Preparation of the tautomers Ia and Ib can take place in a manneranalogous to the preparation of compound I described here. For example,the tautomers Ib can be prepared by the synthetic route shown inScheme 1. In addition, the compound I can be converted into itstautomers Ia with Q=halogen by treating it with a suitable halogenatingagent such as PCl₃ or POCl₃.

Unless indicated otherwise, the reactions described above generally takeplace in a solvent at temperatures between room temperature and theboiling point of the solvent used. Examples of solvents which can beused are ethers such as diethyl ether, diisopropyl ether, methyltert-butyl ether or tetrahydrofuran, dimethylformamide, dimethylsulfoxide, dimethoxyethane, toluene, xylene, acetonitrile, ketones suchas acetone or methyl ethyl ketone, or alcohols such as methanol, ethanolor butanol.

A base is present if desired to neutralize the protons liberated in thereactions. Suitable bases include inorganic bases such as sodium orpotassium carbonate, sodium or potassium bicarbonate, also alcoholatessuch as sodium methoxide, sodium ethoxide, alkali metal hydrides such assodium hydride, organometallic compounds such as butyllithium oralkylmagnesium compounds, or organic nitrogen bases such astriethylamine or pyridine. The latter can simultaneously serve assolvents.

The crude product is isolated in a conventional way, for example byfiltration, removal of the solvent by distillation or extraction fromthe reaction mixture etc. The resulting compounds can be purified in aconventional way, for example by recrystallization from a solvent,chromatography or conversion into an acid addition salt.

The acid addition salts are prepared in a conventional way by mixing thefree base with the appropriate acid, where appropriate in solution in anorganic solvent, for example a low molecular weight alcohol such asmethanol, ethanol or propanol, an ether such as methyl t-butyl ether ordiisopropyl ether, a ketone such as acetone or methyl ethyl ketone or anester such as ethyl acetate.

The inventive compounds of the formula I are highly selective dopamineD₃ receptor ligands which, because of their low affinity for otherreceptors such as D, receptors, D₄ receptors, α1- and/or α2-adrenergicreceptors, muscarinergic receptors, histaminic receptors, opiatereceptors and, in particular, for dopamine D₂ receptors, have fewer sideeffects than classical neuroleptics which comprise D₂ receptorantagonists.

The high affinity of the inventive compounds for D₃ receptors isreflected in very low in vitro K_(i) values of ordinarily less than 100nM (nmol/l) and especially of less than 50 nM. Binding affinities for D₃receptors can for example be determined via the displacement of[¹²⁵I]-iodosulpride in receptor-binding studies.

Particularly important according to the invention are compounds whoseselectivity K_(i)(D₂)/K_(i)(D₃) is preferably at least 10, even betterat least 30 and particularly advantageously at least 50.Receptor-binding studies on D₁, D₂ and D₄ receptors can be carried outfor example via the displacement of [³H]SCH23390, [¹²⁵I]iodosulpride and[¹²⁵I]spiperone.

The compounds of the invention additionally show lower inhibition of themitochondrial respiratory chain, i.e. mitochondrial respiration isinhibited by the compounds I only at comparatively high plasma levels.Inhibition of mitochondrial respiration is observed with the compoundsof the invention in vitro only at concentrations of >50 μM, frequentlyof >100 μM and specifically at concentrations of >200 μM (IC₅₀ values).

The compounds of the invention additionally show comparatively lowplasma protein binding.

The compounds can, because of their binding profile, be used for thetreatment of conditions which respond to dopamine D₃ ligands, i.e. theyare effective for the treatment of those disorders or conditions wherean influencing (modulation) of dopamine D₃ receptors leads to animprovement in the clinical condition or to cure of the disease.Examples of such conditions are disorders or conditions of the centralnervous system.

Disorders or conditions of the central nervous system mean disordersaffecting the spinal cord or, in particular, the brain. The term“disorder” in the sense according to the invention refers toabnormalities which are usually regarded as pathological states orfunctions and may reveal themselves in the form of particular signs,symptoms and/or dysfunctions. The inventive treatment may be directed atindividual disorders, i.e. abnormalities or pathological states, but itis also possible for a plurality of abnormalities, which are causallyconnected together where appropriate, to be combined into patterns, i.e.syndromes, which can be treated according to the invention.

The disorders which can be treated according to the invention include inparticular psychiatric and neurological disorders. These comprise inparticular organic disorders, symptomatic disorders included, such aspsychoses of the acute exogenous type or associated psychoses with anorganic or exogenous cause, e.g. associated with metabolic disorders,infections and endocrinopathies; endogenous psychoses such asschizophrenia and schizotypal and delusional disorders; affectivedisorders such as depressions, mania and manic/depressive states; andcombined forms of the disorders described above; neurotic and somatoformdisorders, and disorders associated with stress; dissociative disorders,e.g. deficits, clouding and splitting of consciousness and personalitydisorders; disorders of attention and waking/sleeping behavior, such asbehavioral disorders and emotional disorders starting in childhood andadolescence, e.g. hyperactivity in children, intellectual deficits,especially attention deficit disorders, disorders of memory andcognition, e.g. learning and memory impairment (impaired cognitivefunction), dementia, narcolepsy and sleeping disorders, e.g. restlesslegs syndrome; developmental disorders; anxiety states; delirium;disorders of the sex life, e.g. male impotence; eating disorders, e.g.anorexia or bulimia; addiction; and other undefined psychiatricdisorders.

The disorders which can be treated according to the invention alsoinclude parkinsonism and epilepsy and, in particular, the affectivedisorders associated therewith.

Addictive disorders include the psychological disorders and behavioraldisorders caused by the abuse of psychotropic substances such aspharmaceuticals or drugs, and other addictive disorders such as, forexample, compulsive gambling (impulse control disorders not elsewhereclassified). Examples of addictive substances are: opioids (e.g.morphine, heroin, codeine); cocaine; nicotine; alcohol; substances whichinteract with the GABA chloride channel complex, sedatives, hypnotics ortranquilizers, for example benzodiazepines; LSD; cannabinoids;psychomotor stimulants such as 3,4-methylenedioxy-N-methylamphetamine(Ecstasy); amphetamine and amphetamine-like substances such asmethylphenidate or other stimulants, including caffeine. Addictivesubstances requiring particular attention are opioids, cocaine,amphetamine or amphetamine-like substances, nicotine and alcohol.

With a view to the treatment of addictive disorders, the inventivecompounds of the formula I which are particularly preferred are thosewhich themselves have no psychotropic effect. This can also be observedin a test on rats which reduce the self-administration of psychotropicsubstances, for example cocaine, after administration of compounds whichcan be used according to the invention.

According to a further aspect of the present invention, the inventivecompounds are suitable for the treatment of disorders the causes ofwhich can at least in part be attributed to an abnormal activity ofdopamine D₃ receptors.

According to another aspect of the present invention, the treatment isdirected in particular at those disorders which can be influenced by abinding of, preferably exogenously added, binding partners (ligands) todopamine D₃ receptors in the sense of an expedient medical treatment.

The conditions which can be treated with the inventive compounds arefrequently characterized by a progressive development, i.e. the statesdescribed above change over the course of time, the severity usuallyincreasing and, where appropriate, states possibly interchanging orother states being added to previously existing states.

The inventive compounds can be used to treat a large number of signs,symptoms and/or dysfunctions associated with the disorders of thecentral nervous system and in particular the aforementioned states.These include for example a distorted relation to reality, lack ofinsight and the ability to comply with the usual social norms anddemands of life, changes in behavior, changes in individual urges suchas hunger, sleep, thirst etc. and in mood, disorders of memory andassociation, personality changes, especially emotional lability,hallucinations, ego disturbances, incoherence of thought, ambivalence,autism, depersonalization or hallucinations, delusional ideas, staccatospeech, absence of associated movement, small-step gait, bent posture oftrunk and limbs, tremor, mask-like face, monotonous speech, depression,apathy, deficient spontaneity and irresolution, reducedassociationability, anxiety, nervous agitation, stammering, socialphobia, panic disorders, withdrawal syndromes associated withdependence, expansive syndromes, states of agitation and confusion,dysphoria, dyskinetic syndromes and tic disorders, e.g. Huntington'schorea, Gilles de Ia Tourette syndrome, vertigo syndromes, e.g.peripheral postural, rotational and vestibular vertigo, melancholia,hysteria, hypochondria and the like.

A treatment in the sense according to the invention includes not onlythe treatment of acute or chronic signs, symptoms and/or dysfunctionsbut also a preventive treatment (prophylaxis), in particular asrecurrence or episode prophylaxis. The treatment may be symptomatic, forexample directed at suppression of symptom. It may take placeshort-term, be directed at the medium term or may also be a long-termtreatment, for example as part of maintenance therapy.

The inventive compounds are preferably suitable for the treatment ofdisorders of the central nervous system, especially for the treatment ofaffective disorders; neurotic disorders, stress disorders and somatoformdisorders and psychoses and specifically for the treatment ofschizophrenia and depression. Owing to their high selectivity inrelation to the D₃ receptor, the inventive compounds are also for thetreatment of renal function disorders, especially of renal functiondisorders caused by diabetes mellitus (see WO 00/67847).

The inventive use of the described compounds comprises a method withinthe scope of the treatment. This entails the individual to be treated,preferably a mammal, in particular a human or agricultural or domesticanimal, being given an effective amount of one or more compounds,usually formulated in accordance with pharmaceutical and veterinarypractice. Whether such a treatment is indicated, and the form it is totake, depends on the individual case and is subject to a medicalassessment (diagnosis) which takes account of the signs, symptoms and/ordysfunctions present, the risks of developing certain signs, symptomsand/or dysfunctions, and other factors.

The treatment usually takes place by administration once or more thanonce a day, where appropriate together or alternately with other activeingredients or active ingredient-containing products, so that anindividual to be treated is given a daily dose preferably of about 0.1to 1000 mg/kg of body weight on oral administration or of about 0.1 to100 mg/kg of body weight on parenteral administration.

The invention also relates to the production of pharmaceuticalcompositions for the treatment of an individual, preferably a mammal, inparticular a human or agricultural or domestic animal. Thus, the ligandsare usually administered in the form of pharmaceutical compositionswhich comprise a pharmaceutically acceptable excipient with at least oneligand of the invention and, where appropriate, further activeingredients. These compositions can be administered for example by theoral, rectal, transdermal, subcutaneous, intravenous, intramuscular orintranasal route.

Examples of suitable pharmaceutical formulations are solidpharmaceutical forms such as oral powders, dusting powders, granules,tablets, especially film-coated tablets, pastilles, sachets, cachets,sugar-coated tablets, capsules such as hard and soft gelatin capsules,suppositories or vaginal pharmaceutical forms, semisolid pharmaceuticalforms such as ointments, creams, hydrogels, pastes or patches, andliquid pharmaceutical forms such as solutions, emulsions, especiallyoil-in-water emulsions, suspensions, for example lotions, preparationsfor injection and infusion, eye drops and ear drops. Implanted deliverydevices can also be used to administer inhibitors of the invention. Afurther possibility is also to use liposomes or microspheres.

The compositions are produced by mixing or diluting inhibitors of theinvention usually with an excipient. Excipients may be solid, semisolidor liquid materials which serve as vehicle, carrier or medium for theactive ingredient.

Suitable excipients are listed in the relevant pharmaceuticalmonographs. The formulations may additionally comprise pharmaceuticallyacceptable carriers or conventional excipients such as lubricants;wetting agents; emulsifying and suspending agents; preservatives;antioxidants; antiirritants; chelating agents; tablet-coating aids;emulsion stabilizers; film formers; gel formers; odor-masking agents;masking flavors; resins; hydrocolloids; solvents; solubilizers;neutralizers; permeation promoters; pigments; quaternary ammoniumcompounds; refatting and superfatting agents; ointment, cream or oilbases; silicone derivatives; spreading aids; stabilizers; sterilants;suppository bases; tablet excipients, such as binders, fillers,lubricants, disintegrants or coatings; propellants; desiccants;opacifiers; thickeners; waxes; plasticizers; white oils. An arrangementconcerning this is based on expert knowledge as set forth for example inFiedler, H. P., Lexikon der Hilfsstoffe für Pharmazie, Kosmetik undangrenzende Gebiete, 4th edition, Aulendorf: ECV-Editio-Kantor-Verlag,1996.

The following examples serve to illustrate the invention withoutlimiting it.

The nuclear magnetic resonance spectral properties (NMR) relate tochemical shifts (δ) expressed in parts per million (ppm). The relativearea for the shifts in the ¹H NMR spectrum corresponds to the number ofhydrogen atoms for a particular functional type in the molecule. Thenature of the shift in terms of multiplicity is indicated as singlet(s), broad singlet (s. br.), doublet (d), broad doublet (d br.), triplet(t), broad triplet (t br.), quartet (q), quintet (quint.), multiplet(m).

PREPARATION EXAMPLES Example 11-(3-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}propyl)-4-mercapto-5-methylpyrimidin-2(1H)-one1.14-[4-(3-Azidopropyl)piperazin-1-yl]-2-tert-butyl-6-(trifluoromethyl)pyrimidine

2.4 g (36.9 mmol) of sodium azide were added to 13.5 g (36.9 mmol) of2-tert-butyl-4-[4-(3-chloropropyl)piperazin-1-yl]-6-(trifluoromethyl)pyrimidine(DE 197 35 410) in 60 ml of N,N-dimethylformamide (DMF), and the mixturewas stirred at 70° C. for 3 hours. The reaction mixture was allowed tocool to room temperature, the mixture was poured into saturated brine,and the aqueous mixture was extracted with ethyl acetate. The organicphase was washed three times with an NaCl solution, dried over Na₂SO₄,filtered to remove the desiccant and concentrated in vacuo. Yield: 13.7g.

ESI-MS: 373.1, [M+H⁺]=372.1, 186.6;

1.23-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}propan-1-aminehydrochloride

13.7 g (36.89 mmol) of4-[4-(3-azidopropyl)piperazin-1-yl]-2-tert-butyl-6-(trifluoromethyl)pyrimidinefrom Example 1.1 in 200 ml of methanol and 0.3 g of Pd/carbon (10%) werestirred under a hydrogen atmosphere at room temperature for 12 hours.The catalyst was filtered off through kieselghur, the resulting filtratewas filtered, and the clear solution was concentrated. The residue wasdissolved in diethyl ether, and a solution of HCl in diethyl ether wasadded, whereupon a precipitate separated out. The hydrochloride wasfiltered off with suction, washed with diethyl ether and dried undernitrogen and then in vacuo at 40° C. Yield: 12.7 g.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 11.62 (1H, s br.), 8.23 (1H, s. br.),7.23 (1H, s.), 4.67 (1H, s. br.), 3.55 (3H, d br.), 3.32-2.88 (2+2+1H, mbr.), 2.10 (1H, quint.), 1.30 (9H, s.).

1.31-(3-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}propyl)-4-mercapto-5-methylpyrimidin-2(1H)-one

0.7 g (2.7 mmol) of ethyl(2E)-2-methyl-3-piperidin-1-ylprop-2-enethioylcarbamate (WO 00/61579),0.9 g (2.6 mmol) of3-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}propan-1-aminehydrochloride from Example 1.2 and 0.6 g (5.5 mmol) ofN-methylmorpholine in 20 ml of methanol were stirred at room temperatureunder a nitrogen atmosphere for 12 hours. Insolubles were removed byfiltration, washed three times with methanol and water and thenrecrystallized from ethyl acetate. Drying in vacuo at 50° C. resulted in0.5 g of the title compound.

ESI-MS: 472.1, [M+H⁺]=471.1, 236.1;

¹H NMR (360 MHz, DMSO-d₆) δ (ppm): 12.33 (1H, s.), 7.57 (1H, s.), 7.48(1H, s.), 6.81 (1H, s.), 4.62 (2H, s br.), 3.98 (2H, t), 3.84 (2H, tbr.), 3.65 (2H, d br.), 3.18 (2H, t br.), 2.36 (2H, quint.), 2.08 (3H,s), 1.33 (9H, s).

Example 21-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-4-mercapto-5-methylpyrimidin-2(1H)-one

0.7 g of the title compound was obtained in analogy to Example 1 from1.2 g (3.3 mmol) of4-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butan-1-amine.

ESI-MS: 486.4, [M+H⁺]=485.4, 243.3;

¹H NMR (360 MHz, CDCl₃) δ (ppm: 10.33 (1H, s. br.), 7.00 (1H, s.), 6.57(1H, s.), 3.60-3.80 (6H, m), 2.52 (4H, t), 2.44 (2H, t), 2.10 (3H, s),1.78 (2H, quint.), 1.58 (2H, quint.), 1.33 (9H, s).

Example 3 1-{4-[4-(Benzylthio)-5-methyl-2-oxopyrimidin-1(2H)-yl]butyl}-4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-iumchloride

145.4 mg (0.3 mmol) of1-(4-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-4-mercapto-5-methylpyrimidin-2(1H)-onefrom Example 2 and 78.8 mg (0.6 mmol) of K₂CO₃ were stirred in 10 ml ofN,N-dimethylformamide (DMF) for 20 minutes. Then 77.0 mg (0.5 mmol) ofbenzyl bromide were added dropwise. The reaction mixture was stirred atroom temperature for 2 days and then added to water and extracted withethyl acetate. Drying of the organic phase over Na₂SO₄, removal of thedesiccant by filtration and concentration in vacuo were followed bystirring the resulting solid with diethyl ether and filtration withsuction. The residue after concentration of the mother liquor in vacuowas taken up in a little CH₂Cl₂, and a solution of HCl in diethyl etherwas added, whereupon the required product precipitated as hydrochloride.The hydrochloride was filtered off with suction and washed with diethylether, and the title compound was dried in vacuo at 40° C. Yield: 25 mg.

ESI-MS: [M+Na⁺]=597.3, 576.2, [M+H⁺]=575.2, 288.1.

¹H NMR (500 MHz, DMSO-d₆) δ (ppm: 10.72 (1H, s. br.), 7.85 (1H, s.),7.40 (2H, d), 7.30 (2H, t), 7.24 (1H, t), 7.21 (1H, s.), 4.38 (2H, s.),3.79 (2H, m), 3.55 (2H, d br.), 3.51-3.40 (2H, m br.), 3.15-3.00 (4H,m), 1.93 (3H, s.), 1.70 (4H, s. br.), 1.31 (9H, s.).

Example 41-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]-4-{4-[5-methyl-4-(methylthio)-2-oxopyrimidin-1(2H)-yl]butyl}piperazin-4-ium chloride

96.9 mg (0.8 mmol) of ethyldiisopropylamine (DIPEA) were added to 145.4mg (0.3 mmol) of1-(4-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-4-mercapto-5-methylpyrimidin-2(1H-onefrom Example 2 in 12 ml of methanol under nitrogen, and the reactionmixture was stirred for 20 minutes. Then 183.1 mg (1.3 mmol) of methyliodide were added dropwise, and the reaction mixture was stirred at roomtemperature for 12 hours. Water was added to the reaction mixture, andthe aqueous mixture was extracted twice with ethyl acetate. The residueafter drying of the organic phase over Na₂SO₄, removal of the desiccantby filtration and evaporation of the solvent to dryness in vacuo wastaken up in diethyl ether. A solution of HCl in diethyl ether was added,whereupon the required product precipitated as hydrochloride. Thehydrochloride was filtered off with suction and washed with diethylether, and the title compound was dried in vacuo at 40° C. Yield: 85.0mg.

ESI-MS: [M+Na⁺]=521.3, 500.3, [M+H⁺]=499.2, 250.1;

¹H NMR (500 MHz, DMSO-d₆) δ (ppm: 10.85 (1H, s. br.), 7.87 (1H, s.),7.27 (1H, s.), 3.83 (3H, t), 3.60 (2H, d br.), 3.55-3.46 (2H, m),3.18-3.04 (4H, m), 2.52 (3H, s), 2.00 (3H, s), 1.73 (4H, s. br.), 1.35(9H, s.).

Example 51-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]-4-[4-(4-hydroxy-5-methyl-2-oxopyrimidin-1(2H)-yl)butyl]piperazin-4-ium chloride

Method 1

40.9 mg (1.2 mmol) of H₂O₂ were added dropwise to 50.0 mg (0.1 mmol) of1-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]-4-{4-[5-methyl-4-(methylthio)-2-oxopyrimidin-1(2H)-yl]butyl}piperazine hydrochloride from Example 4 in 5 ml of glacialacetic acid at 10° C., and the mixture was stirred at room temperaturefor 3 hours. Then a further 40.9 mg (1.2 mmol) of H₂O₂ were addeddropwise, and the reaction mixture was stirred at room temperature for afurther six hours. Water was added to the reaction mixture, and then theaqueous mixture was extracted twice with dichloromethane. The organicphase was washed with an aqueous sodium thiosulfate solution until freeof peroxides and then extracted once with dilute aqueous sodiumcarbonate solution and once with saturated aqueous brine. The residueafter drying of the organic phase over Na₂SO₄, removal of the desiccantby filtration and evaporation of the solvent to dryness in vacuo wastaken up in diethyl ether. A solution of HCl in diethyl ether was added,whereupon the required product precipitated as hydrochloride. Thehydrochloride was filtered off with suction and washed with diethylether, and the title compound was dried in vacuo at 40° C. Yield: 25.0mg.

Method 2

5.2.1 1-(4-Chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one

10.1 g (80.0 mmol) of 4-hydroxy-5-methylpyrimidin-2(1H-one (thymine) in300 ml of dimethyl sulfoxide (DMSO) and 11.1 g (80.0 mmol) of K₂CO₃ werestirred at room temperature for 1 hour. Then 13.7 g (80.0 mmol) of1-bromo-4-chlorobutane were added dropwise to the mixture, and thereaction mixture was stirred at room temperature for 5 hours. Water wasadded to the reaction mixture, which was then extracted with ethylacetate. The aqueous phase was then neutralized and extracted withmethylene chloride. Drying of the organic phase, removal of thedesiccant by filtration and evaporation of the solvent to dryness invacuo resulted in 7.1 g of1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one.

ESI-MS: 219.1, [M+H⁺]=217.1;

¹H NMR (500 MHz, CDCl₃) δ (ppm: 9.97 (1H, s.), 7.02 (1H, s.), 3.74 (2H,t), 3.55 (2H, t), 1.93 (3H, s), 2.02-1.75 (4H, m).

5.2.21-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]-4-[4-(4-hydroxy-5-methyl-2-oxopyrimidin-1(2H)-yl)butyl]piperazin-4-ium chloride

1.5 g (7.0 mmol) of1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one from Example5.2.1, 2.0 g (7.0 mmol) of2-tert-butyl-4-piperazin-1-yl-6-(trifluoromethyl)pyrimidine (DE 197 35410) and 1.4 g (14.0 mmol) of NEt₃ in 100 ml of N,N-dimethylformamide(DMF) were stirred at 110° C. for 24 hours. Then ethyl acetate wasadded, and the mixture was washed twice with water. The combined organicphases were dried over Na₂SO₄, filtered to remove the desiccant andconcentrated in vacuo. The oily residue was purified by chromatographyon silica gel (eluent: dichloromethane:methanol 95:5 v/v), and stirredwith pentane and filtered off with suction. The solid was taken up in alittle methylene chloride, and a solution of HCl in diethyl ether wasadded, whereupon the required product precipitated as hydrochloride. Thehydrochloride was filtered off with suction and washed with diethylether, and the title compound was dried in vacuo at 40° C. Yield: 1.1 g.

ESI-MS: 470.5, [M+H⁺]=469.5, 235.3;

¹H NMR (500 MHz, DMSO-d₆) δ (ppm: 11.57 (1H, s. br.), 11.23 (1H, s.),7.62 (1H, s.), 7.24 (1H, s.), 4.68 (2H, s. br.), 3.65 (2H, t), 3.55 (4H,d br.), 3.14-3.00 (4H, m), 1.82-1.71 (3+2H, s+m), 1.68-1.59 (2H, m),1.31 (9H, s).

Example 61-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-methylpyrimidin-2(1H)-one6.1 5-Methylpyrimidin-2(1H)-one (Chem. Ztg. 1977, 6, 305-7)

11.4 g (0.1 mol) of (2Z)-3-ethoxy-2-methylprop-2-enal(3-ethoxymethacrolein), 6.0 g (0.1 mol) of carbamide (urea) and 10 ml ofconc. HCl solution in 20 ml of ethanol were heated under reflux for 3.5hours. The reaction mixture was then allowed to cool and was cooled withice-water, whereupon a precipitate formed. The precipitated crystalswere filtered off with suction, washed with ethanol and dried at 40° C.in vacuo. Yield: 11.0 g.

ESI-MS: [2M+Na⁺]=243.1, [M+H⁺]=111.1;

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.68 (2H, s.), 2.12 (3H, s.).

6.2 1-(4-Chlorobutyl)-5-methylpyrimidin-2(1H)-one

10.5 g (95.0 mmol) of 5-methylpyrimidin-2(1H)-one from Example 6.1, 16.3g (95.0 mmol) of 1-bromo-4-chlorobutane and 39.4 g (285.0 mmol) of K₂CO₃in 200 ml of dimethyl sulfoxide were stirred at room temperature for 12hours. The reaction mixture was added to ice-water, and the aqueousmixture was extracted twice with diethyl ether. The aqueous phase wasextracted twice with methylene chloride. The methylene chloride phasewas dried over Na₂SO₄ and filtered to remove the desiccant, and thesolvent was evaporated to dryness in vacuo. The resulting solid residuewas stirred with diethyl ether, and the precipitate was filtered offwith suction, washed with diethyl ether and dried. Yield: 5.0 g.

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.46 (1H, d), 7.46 (1H, d), 3.90 (2H,t), 3.57 (2H, t), 2.11 (3H, s.), 1.95 (2H, quint.), 1.88-1.78 (2H,quint.).

6.31-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-methylpyrimidin-2(1H)-one

The title compound was obtained in analogy to Example 5.2.2 startingfrom 1.4 g (5.0 mmol) of 1-(4-chlorobutyl)-5-methylpyrimidin-2(1H)-onefrom Example 6.2; yield: 0.5 g.

ESI-MS: 454.2, [M+H⁺]=453.3, 227.1;

¹H NMR (500 MHz, DMSO-d₆) δ (ppm: 8.41 (1H, s.), 7.97 (1H, s.), 6.93(1H, s.), 3.82 (2H, t), 3.69 (4H, s. br.), 2.42 (4H, m sym.), 2.35 (2H,t), 2.05 (3H, s), 1.70 (2H, quint.), 1.48 (2H, quint.), 1.28 (9H, s).

Example 71-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-methyl-4-phenoxypyrimidin-2(1H)-one7.11-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-methyl-2-oxo-1,2-dihydropyrimidin-4-ylthiocyanate

A solution of KCN (325.6 mg, 5.0 mmol) in 5% strength NaHCO₃ solution (7ml) was added to 484.6 mg (1.0 mmol) of1-(4-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-4-mercapto-5-methylpyrimidin-2(1H)-onefrom Example 2 in 20 ml of methylene chloride. Then a mixture of 2.0 mgof 18-crown-6 and 105.9 mg (1.0 mmol) of BrCN, in the minimum amount ofmethylene chloride necessary to dissolve, was added dropwise at 0° C.The organic phase was then separated off and washed twice with saturatedaqueous brine. The organic phase was dried over Na₂SO₄ and filtered toremove the desiccant, and the solvent was evaporated to dryness invacuo; yield: 420.0 mg.1-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-methyl-2-oxo-1,2-dihydropyrimidin-4-ylthiocyanate was employed without additional purification in the nextstep.

7.21-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-methyl-4-phenoxypyrimidin-2(1H)-one

81.3 mg (0.9 mmol) of phenol and 325.5 mg (2.4 mmol) of K₂CO₃ were addedto 400.0 mg (0.78 mmol) of1-(4-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-methyl-2-oxo-1,2-dihydropyrimidin-4-ylthiocyanate from Example 7.1 in 40 ml of acetonitrile and 500.0 mg ofmolecular sieves (3 Å). The reaction mixture was then stirred at roomtemperature for 12 hours. Insolubles were filtered off, methylenechloride was added to the filtrate, followed by extraction with aqueousbrine. The residue after drying of the organic phase, removal of thedesiccant by filtration and evaporation of the solvent in vacuo wastaken up in 100 ml of diisopropyl ether and heated. The precipitate wasfiltered off with suction and the mother liquor was concentratedsomewhat. The mother liquor was then mixed with pentane and cooled in anice bath. The precipitated solid was filtered off with suction, washedand dried in vacuo at 40° C., resulting in 120 mg of the title compound.

ESI-MS: 546.3, [M+H⁺]=545.3, 273.1;

¹H NMR (500 MHz, CDCl₃) δ (ppm: 7.37 (2H, t), 7.32 (1H, s.), 7.20 (1H,t), 7.13 (2H, d), 6.56 (1H, s.), 3.85 (2H, t), 3.69 (4H, s br.), 2.50(4H, m sym.), 2.41 (2H, t), 2.12 (3H, s.), 1.79 (2H, quint.), 1.57 (2H,quint.), 1.32 (9H, s.).

Example 81-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-4-methylpyrimidin-2(1H)-one

8.1 4-Methylpyrimidin-2(1H)-one (Analogous to Aust. J. Chem. 1968, 21,243-55) 20.0 ml of conc. HCl were added dropwise to 26.4 g (0.2 mol) of4,4-dimethoxybutan-2-one in 40 ml of ethanol and 12.0 g (0.2 mol) ofurea. A clear brown solution was produced after a short time, and ayellow precipitate separated out after a further 10 minutes. Thereaction mixture was heated under reflux for 1.5 hours and then allowedto cool (ice-water bath). The precipitated crystals were then filteredoff with suction and washed with ethanol, and the crystals were dried invacuo at 40° C.; yield: 22.0 g.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm: 8.61 (1H, d), 6.81 (1H, d), 2.59 (3H,s.).

8.2 1-(4-Chlorobutyl)-4-methylpyrimidin-2(1H)-one

5.1 g of 1-(4-chlorobutyl)-4-methylpyrimidin-2(1H)-one were obtained inanalogy to Example 6.2 from 12.1 g (0.1 mol) of4-methylpyrimidin-2(1H)-one.

ESI-MS: [M+H⁺]=201.1;

¹H NMR (400 MHz, CDCl₃) δ (ppm: 7.52 (1H, d), 6.22 (1H, d), 3.92 (2H,t), 3.57 (2H, t), 2.39 (3H, s.), 1.94 (2H, quint.), 1.86-1.74 (2H, m).

8.31-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-4-methylpyrimidin-2(1H)-one

0.25 g of the title compound was prepared in analogy to Example 5.2.2from 1.1 g (5.5 mmol) of 1-(4-chlorobutyl)-4-methylpyrimidin-2(1H)-one.

ESI-MS: 454.2, [M+H⁺]=453.3, 227.1;

¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.48 (1H, d), 6.56 (1H, s.), 6.19 (1H,d), 3.90 (2H, t), 3.70 (4H, s. br.), 2.50 (4H, m sym.), 2.43 (2H, t),2.40 (3H, s), 1.83 (2H, quint.), 1.59 (2H, quint.), 1.33 (9H, s.).

Example 91-{4-[4-(2,6-ditert-Butylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-hydroxy-5-methylpyrimidin-2(1H)-one

170.0 mg of the title compound were obtained in analogy to Example 5.2.2from 390.0 mg (1.8 mmol) of1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one from Example5.2.1 and 414.6 mg (1.5 mmol) of2,4-ditert-butyl-6-piperazin-1-ylpyrimidine.

ESI-MS: 458.4, [M+H⁺]=457.4, 229.1;

¹H NMR (500 MHz, CDCl₃) δ (ppm: 9.29 (1H, s br.), 6.97 (1H, s.), 6.24(1H, s), 3.72 (2H, t), 3.64 (4H, m sym.), 2.52 (4H, m sym.), 2.44 (2H,t), 1.93 (3H, s), 1.74 (2H, quint.), 1.58 (2H, quint.), 1.27 (9H, s.),1.33 (9H, s.).

Example 101-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-hydroxy-5-methylpyrimidin-2(1H)-one

220.0 mg of the title compound were obtained in analogy to Example 5.2.2from 390.0 mg (1.8 mmol) of1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one from Example5.2.1 and 393.6 mg (1.5 mmol) of2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine.

ESI-MS: 444.2, [M+H⁺]=443.4, 222.1;

¹H NMR (500 MHz, CDCl₃) δ (ppm: 9.01 (1H, s.), 6.96 (1H, s.), 6.11 (1H,s.), 3.72 (2H, t), 3.62 (4H, m sym.), 2.57-2.49 (2+4H, m), 2.41 (2H, t),1.93 (3H, s), 1.58 (2H, quint.), 1.31 (9H, s.).

Example 114-(Benzylamino)-1-(4-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-methylpyrimidin-2(1H)-one

0.5 g of the title compound was obtained in analogy to Example 5.2.2from 2.0 g (4.0 mmol) of1-(4-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-methyl-2-oxo-1,2-dihydropyrimidin-4-ylthiocyanate from Example 7.1 and 0.5 g (4.4 mmol) of benzylamine.

ESI-MS: 559.5, [M+H⁺]=558.5, 279.8;

¹H NMR (500 MHz, CDCl₃) δ (ppm: 7.38 (1H, s), 7.34-7.24 (5H, m), 7.03(1H, s. br.), 6.64 (1H, s.), 4.68 (2H, m sym.), 3.83 (2H, m), 3.11 (4H,s. br.), 2.85 (4H, s. br.), 2.04 (3H, s.), 1.84 (4H, s. br.), 1.31 (9H,s.).

Example 121-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]-4-{4-[4-(dimethylamino)-5-methyl-2-oxopyrimidin-1(2H)-yl]butyl}piperazin-4-ium chloride

0.7 g of the title compound was obtained in analogy to Example 7.2 from1.0 g (2.0 mmol) of1-(4-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-methyl-2-oxo-1,2-dihydropyrimidin-4-ylthiocyanate from Example 7.1 and dimethylamine (2M in methanol, 1.1 ml).

ESI-MS: [M+H⁺]=496.5, 248.7;

¹H NMR (500 MHz, DMSO-d₆) δ (ppm: 11.61 (1H, s. br.), 7.96 (1H, s.),7.21 (1H, s), 3.76 (2H, t), 3.54 (2H, d br.), 3.27 (6H, s), 3.12-3.00(2+2H, m), 2.20 (3H, s), 1.75-1.67 (2+2H, m), 1.30 (9H, s).

Example 131-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl}butyl)-4-hydroxypyrimidin-2(1H)-one

0.6 g of the title compound was obtained in analogy to Example 7.2 from1.0 g (4.0 mmol) of 1-(4-bromobutyl)pyrimidine-2,4(1H,3H)-dione (J. Am.Chem. Soc. 1993, 115, 7636).

ESI-MS: 456.2, [M+H⁺]=455.3, 228.1;

¹H NMR (500 MHz, CDCl₃) δ (ppm: 10.04 (1H, s. br.), 7.15 (1H, d), 6.58(1H, s.), 5.68 (1H, d), 3.75 (2H, t), 3.70 (4H, s. br.), 2.51 (4H, t),2.43 (2H, t), 1.74 (2H, quint.), 1.57 (2H, quint.), 1.33 (9H, s).

Example 144-tert-Butyl-1-(4-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)pyrimidin-2(1H)-one14.1 4-tert-Butyl-1-(4-chlorobutyl)pyrimidin-2(1H)-one

13.4 g of 4-tert-butyl-1-(4-chlorobutyl)pyrimidin-2(1H)-one wereobtained in analogy to Example 6.2 from 16.7 g (0.1 mol) of4-tert-butylpyrimidin-2(1H)-one.

¹H NMR (500 MHz, CDCl₃) δ (ppm: 7.54 (1H, d), 6.38 (1H, d), 3.92 (2H,t), 3.59 (2H, t), 1.97 (2H, quint.), 1.87 (2H, quint.), 1.30 (9H, s).

14.24-tert-Butyl-1-(4-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)pyrimidin-2(1H)-one

0.8 g of the title compound was obtained in analogy to Example 5.2.2from 1.21 g (5.0 mmol) of4-tert-butyl-1-(4-chlorobutyl)pyrimidin-2(1H)-one from Example 14.1.

ESI-MS: 496.4, [M+H⁺]=495.4, 248.1;

¹H NMR (500 MHz, CDCl₃) δ (ppm: 7.52 (1H, d), 6.58 (1H, s), 6.37 (1H,d), 3.91 (2H, t), 3.70 (4H, s br.), 2.48 (4H, t), 2.41 (2H, t), 1.86(2H, quint.), 1.59 (2H, quint.), 1.35 (9H, s), 1.30 (9H, s).

Example 151-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]-4-{4-[2-oxo-4-(trifluoromethyl)pyrimidin-1(2H)-yl]butyl}piperazin-4-ium chloride 15.11-(4-Chlorobutyl)-4-(trifluoromethyl)pyrimidin-2(1H)-one

4.6 g (28.3 mmol) of 2-hydroxy-4-trifluoromethylpyrimidine were stirredin 60 ml of N,N-dimethylformamide (DMF) and 3.9 g (28.3 mmol) of K₂CO₃at room temperature for 1 hour. Then 4.9 g (28.3 mmol) of1-bromo-4-chlorobutane were added dropwise, and the reaction mixture wasstirred at room temperature for 6 hours. Water was then added to thereaction mixture, and the aqueous mixture was extracted with diethylether. The aqueous phase was made alkaline by adding NaOH, and theaqueous phase was extracted with methylene chloride. The organic phasewas then dried, the desiccant was removed by filtration, and the solventwas evaporated to dryness in vacuo; yield: 1.7 g.

ESI-MS: [M+Na⁺]=257.0, [M+H⁺]=255.1;

15.21-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]-4-{4-[2-oxo-4-(trifluoromethyl)-pyrimidin-1(2H)-yl]butyl}piperazin-4-ium chloride

0.53 g of the title compound was obtained in analogy to Example 5.2.2from 0.6 g (2.36 mmol) of1-(4-chlorobutyl)-4-(trifluoromethyl)pyrimidin-2(1H)-one from Example15.1.

ESI-MS: [M+Na⁺]=529.3, 508.3, [M+H⁺]=507.2, 254.1;

¹H NMR (500 MHz, DMSO-d₆) δ (ppm): 11.37 (1H, s br.), 8.69 (1H, d), 7.20(1H, s), 6.89 (1H, d), 4.23 (4H, s br.), 3.98 (2H, t), 3.54 (4H, m br.),3.14-2.98 (4H, m br.), 1.75 (4H, s br.), 1.30 (9H, s).

Example 161-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]-4-[4-(5-fluoro-2,4-dioxo-3,4-dihydro-pyrimidin-1(2H)-yl)butyl]piperazin-4-ium chloride 16.11-(4-Chlorobutyl)-5-fluoropyrimidine-2,4(1H,3H)-dione

2.6 g (15.0 mmol) of 1-bromo-4-chlorobutane were added dropwise to asolution of 1.95 g (15.0 mmol) of 2,4-dihydroxy-5-fluoropyrimidine in 50ml of dimethyl sulfoxide and 20.0 ml of N,N-dimethylformamide (DMF) at0° C. 2.07 g (15.0 mmol) of K₂CO₃ were added in portions over the courseof 1 hour, and the mixture was stirred at 20° C. for 1 hour (dialkylatedproduct is already identifiable). Water was then added to the reactionmixture, and the aqueous mixture was extracted twice with diethyl etherand twice with methylene chloride. The aqueous phase was adjusted to pH3-4 with hydrochloric acid and then the aqueous phase was extracted withmethylene chloride. The organic phase was then dried, the desiccant wasremoved by filtration, and the solvent was evaporated to dryness invacuo; yield: 0.6 g.1-(4-Chlorobutyl)-5-fluoropyrimidine-2,4(1H,3H)-dione was employedwithout further purification in the next step.

16.21-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]-4-[4-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)butyl]piperazin-4-ium chloride

0.03 g of the title compound was obtained in analogy to Example 5.2.2from 0.66 g (3.00 mmol) of1-(4-chlorobutyl)-5-fluoropyrimidine-2,4(1H,3H)-dione.

ESI-MS: 474.5, [M+H⁺]=473.5, 237.3.

Example 171-{4-[4-(2-tert-Butyl-6-cyclopropylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-hydroxy-5-methylpyrimidin-2(1H)-one

0.18 g of the title compound was obtained in analogy to Example 5.2.2from 0.43 g (2.00 mmol) of1-(4-chlorobutyl)-5-methylpyrimidine-2,4(1H,3H)-dione from step 5.2.1and 0.52 g (2.00 mmol) of2-tert-butyl-4-cyclopropyl-6-piperazin-1-ylpyrimidine.

ESI-MS: 442.5, [M+H⁺]=441.5, 221.3;

¹H NMR (500 MHz, CDCl₃) δ (ppm: 8.80 (1H, s br.), 6.97 (1H, s), 6.15(1H, s), 3.71 (2H, t), 3.62 (4H, t br.), 2.48 (4H, t), 2.40 (2H, t),1.93 (3H, s), 1.81-1.66 (1+2H, m), 1.57 (2H, quint.), 1.27 (9H, s), 1.07(2H, m sym.), 0.85 (2H, m sym.).

Example 181-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile18.11-(4-Chlorobutyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

2.6 g (15.0 mmol) of 1-bromo-4-chlorobutane were added dropwise to asolution of 2.06 g (15.0 mmol) of 5-cyanouracil in 50 ml of dimethylsulfoxide (DMSO) and 20.0 ml of N,N-dimethylformamide (DMF) at 0° C.,and 2.07 g (15.0 mmol) of K₂CO₃ were added in portions over the courseof 1 hour. The mixture was then stirred at 20° C. for 10 minutes(dialkylated product already identifiable). Water was added to thereaction mixture, and then the aqueous mixture was extracted twice withdiethyl ether and twice with methylene chloride. The aqueous phase wasadjusted to pH 3-4 and then extracted with methylene chloride. Themethylene chloride phase was then dried, the desiccant was removed byfiltration, and the solvent was evaporated to dryness in vacuo; yield:0.6 g.1-(4-Chlorobutyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrilewas employed without further purification in the next step.

ESI-MS: [M+H⁺]=228.05.

18.21-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

0.07 g of the title compound was obtained in analogy to Example 5.2.2from 0.68 g (3.00 mmol) of1-(4-chlorobutyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrilefrom Example 18.1.

ESI-MS: 481.5, [M+H⁺]=480.5, 240.7;

¹H NMR (500 MHz, CDCl₃) δ (ppm): 8.02 (1H, s), 6.59 (1H, s), 3.84 (2H,t), 3.71 (4H, s br.), 2.50 (4H, t br.), 2.41 (2H, t), 1.79 (2H, quint.),1.56 (2H, quint.), 1.32 (9H, s).

Example 194-tert-Butyl-1-{4-[4-(2-tert-butyl-6-cyclopropylpyrimidin-4-yl)piperazin-1-yl]butyl}pyrimidin-2(1H)-one

0.11 g of the title compound was obtained in analogy to Example 5.2.2from 0.49 g (2.00 mmol) of4-tert-butyl-1-(4-chlorobutyl)pyrimidin-2(1H)-one from Example 14.1 and0.52 g (2.00 mmol) of2-tert-butyl-4-cyclopropyl-6-piperazin-1-ylpyrimidine.

ESI-MS: 468.5, [M+H⁺]=467.4, 234.2;

¹H NMR (500 MHz, CDCl₃) δ (ppm: 7.51 (1H, d), 6.36 (1H, d), 6.14 (1H,s), 3.91 (2H, t), 3.61 (4H, t br,), 2.46 (4H, t br.), 2.38 (2H, t),1.86-1.74 (2+1H, m), 1.57 (2H, quint.), 1.31 (9H, s), 1.27 (9H, s), 1.07(2H, m sym.), 0.87 (2H, m sym.).

Example 201-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-hydroxypyrimidin-2(1H)-one

1.8 g of the title compound were obtained in analogy to Example 5.2.2from 1.7 mg (8.4 mmol) of 1-(4-chlorobutyl)-4-hydroxypyrimidin-2(1H)-one(obtainable in analogy to the preparation of1-(4-bromobutyl)pyrimidine-2,4(1H,3H)-dione, see Example 13) and 1.84 mg(7.0 mmol) of 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine.

ESI-MS: 430.4, [M+H⁺]=429.4, 215.1;

¹H NMR (500 MHz, CDCl₃) δ (ppm: 9.43 (1H, s br.), 7.13 (1H, d), 6.11(1H, s), 5.68 (1H, d), 3.78 (2H, t), 3.63 (4H, s br.), 2.58-2.48 (4H,m), 2.43 (2H, t), 1.79-1.66 (2+1H, m), 1.57 (2H, quint.), 1.31 (9H, s),0.94 (3H, t).

Example 21 1-[4-(4-tert-Butyl-2-oxopyrimidin-1(2H)-yl)butyl]-4-(2-tert-butyl-6-propylpyrimidin-4-yl)piperazin-1-iumchloride

1.8 g of the title compound were obtained in analogy to Example 5.2.2from 2.04 g (8.40 mmol) of4-tert-butyl-1-(4-chlorobutyl)pyrimidin-2(1H)-one from Example 14.1 and1.84 mg (7.0 mmol) of 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine.

ESI-MS: 470.5, [M+H⁺]=469.4, 235.3, 157.2;

¹H NMR (500 MHz, DMSO-d₆) δ (ppm: 14.13 (1H, s br.), 11.89 (1H, s br.),8.59 (1H, d), 6.73 (1H, d), 5.00 (1H, d br.), 4.47 (1H, d br.), 3.61(3H, d br.), 3.14 (4H, s br.), 2.88 (2H, t), 1.84-1.66 (6H, m), 1.43(9H, s), 1.28 (9H, s), 0.94 (3H, t).

Example 221-{4-[4-(2-tert-Butyl-6-cyclobutylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-hydroxy-5-methylpyrimidin-2(1H)-one

0.11 g of the title compound was obtained in analogy to Example 5.2.2from 0.30 g (1.10 mmol) of2-tert-butyl-4-cyclobutyl-6-piperazin-1-ylpyrimidine.

ESI-MS: 456.4, [M+H⁺]=455.4, 228.2;

¹H NMR (500 MHz, CDCl₃) δ (ppm: 8.88 (1H, s br.), 6.97 (1H, s), 6.11(1H, s), 3.71 (2H, t), 3.63 (4H, s br.), 3.42 (1H, t), 2.49 (4H, t),2.41 (2H, t), 2.27 (4H, m), 2.00 (1H, sext.), 1.92 (3H, s), 1.92-1.84(1H, m), 1.72 (2H, quint.), 1.56 (2H, quint.), 1.32 (9H, s).

Example 231-{4-[4-(2-tert-Butyl-6-cyclobutylpyrimidin-4-yl)piperazin-1-yl]butyl}pyrimidine-2,4(1H,3H)-dione

0.14 g of the title compound was obtained in analogy to Example 5.2.2from 0.28 g (1.40 mmol) of1-(4-chlorobutyl)-4-hydroxypyrimidin-2(1H)-one (obtainable in analogy tothe preparation of 1-(4-bromobutyl)pyrimidine-2,4(1H,3H)-dione, seeExample 13) and 0.30 g (1.10 mmol) of2-tert-butyl-4-cyclobutyl-6-piperazin-1-ylpyrimidine.

ESI-MS: 442.5, [M+H⁺]=441.5;

¹H NMR (500 MHz, CDCl₃) δ (ppm: 7.15 (1H, d), 6.11 (1H, s), 5.69 (1H,d), 3.77 (2H, t), 3.63 (4H, s br.), 3.42 (1H, quint.), 2.51 (4H, t),2.42 (2H, t), 2.32-2.20 (2+2H, m), 2.05-1.84 (1+1H, m), 1.75 (2H,quint.), 1.56 (2H, quint.), 1.31 (9H, s).

Example 241-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-4-phenylpyrimidin-2(1H)-one24.1 2-Chloro-4-phenylpyrimidine

2.78 g (20.14 mmol) of K₂CO₃, 0.21 g (0.18 mmol) oftetrakis(triphenylphosphine)Pd(0) were added to 1.00 g (6.71 mmol) of2,4-dichloropyrimidine and 0.82 g (6.71 mmol) of benzeneboronic acid in29 ml of toluene and 7 ml of methanol, and the reaction mixture wasstirred at room temperature for 3 hours. The residue after concentrationof the reaction mixture was taken up in water/methyl tert-butyl ether.The aqueous phase was then extracted twice with methyl tert-butyl ether.Thereafter the combined organic phase was washed with water and with asaturated aqueous NaCl solution, and the organic phase was dried,filtered to remove the desiccant and concentrated. The solid brownresidue was purified by flash chromatography on silica gel (mobilephase: ethyl acetate/cyclohexane: 10:90); yield: 0.90 g.

¹H NMR (400 MHz, CDCl₃) δ (ppm: 8.64 (1H, d), 8.10 (2H, d), 7.650 (1H,d), 7.58-7.48 (3H, m).

24.2 4-Phenylpyrimidin-2-ol

0.80 g (4.20 mmol) of 2-chloro-4-phenylpyrimidine from Example 24.1 washeated in 3.20 ml of conc. HCl at 100° C. for 1 hour. The mixture wasthen concentrated, suspended in methylene chloride and againconcentrated. Yield: 0.83 g.

ESI-MS: 174.3, [M+H⁺]=173.2;

24.3 1-(4-Chlorobutyl)-4-phenylpyrimidin-2(1H)-one

0.84 g (4.20 mmol) of 4-phenylpyrimidin-2-ol from Example 24.2 wasstirred in 8.4 ml of N,N-dimethylformamide (DMF) and 0.58 g (4.20 mmol)of K₂CO₃ at room temperature for 1 hour. Then 0.72 g (4.20 mmol) of1-bromo-4-chlorobutane was added dropwise, the reaction mixture wasstirred at room temperature for 12 hours, and the reaction mixture wasfiltered and concentrated. The residue was then taken up in toluene andconcentrated, and the residue was again taken up in toluene andconcentrated. The resulting residue was stirred with pentane andfiltered. Yield: 0.74 g.

¹H NMR (400 MHz, CDCl₃) δ (ppm: 8.10 (2H, d), 7.71 (1H, d), 7.63-7.40(3H, m), 6.82 (1H, d), 3.98 (2H, t), 3.58 (2H, t), 2.00 (2H, quint.),1.90 (2H, quint.).

24.41-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-4-phenylpyrimidin-2(1H)-one

0.32 g of the title compound was obtained in analogy to Example 5.2.2from 0.74 g (2.82 mmol) of 1-(4-chlorobutyl)-4-phenylpyrimidin-2(1H)-onefrom Example 24.3.

ESI-MS: [M+H⁺]=515.2, 258.1;

¹H NMR (500 MHz, CDCl₃) δ (ppm): 8.08 (2H, d), 7.86 (1H, d), 7.52 (1H,t), 7.46 (1H, t), 6.79 (1H, d), 6.57 (1H, s), 3.99 (2H, t), 3.69 (4H, sbr.), 2.49 (4H, t), 2.42 (2H, t), 1.89 (2H, quint.), 1.61 (2H, quint.),1.33 (9H, s).

Example 251-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-3,5-dimethylpyrimidine-2,4(1H,3H)-dione25.1 1-(4-Chlorobutyl)-3,5-dimethylpyrimidine-2,4(1H,3H)-dione

2.31 mmol (0.50 g) of1-(4-chlorobutyl)-5-methylpyrimidine-2,4(1H,3H)-dione, 0.65 g (11.54mmol) of KOH and 1.64 g (11.54 mmol) of methyl rodide in 20.5 ml ofdimethyl sulfoxide (DMSO) were stirred at room temperature for 5 hours.Water was added to the reaction mixture, and the aqueous mixture wasextracted three times with methyl tert-butyl ether. The combined organicphase was then washed three times with saturated aqueous brine, and theorganic phase was dried, filtered to remove the desiccant andconcentrated. 0.53 g of a pale cloudy oil was obtained.

ESI-MS: [M+H⁺]=231.15;

25.21-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-3,5-dimethylpyrimidine-2,4(1H,3H)-dione

0.54 g of the title compound was obtained in analogy to Example 5.2.2from 0.53 g (2.30 mmol) of1-(4-chlorobutyl)-3,5-dimethylpyrimidine-2,4(1H,3H)-dione from Example25.1.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 6.98 (1H, s), 6.59 (1H, s), 3.76 (2H,t), 3.70 (4H, s br.), 3.37 (3H, s), 2.50 (3H, t), 2.41 (2H, t), 1.94(3H, s), 1.74 (2H, quint.), 1.56 (2H, quint.), 1.33 (9H, s).

Example 261-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-methyl-4-phenylpyrimidin-2(1H)-one26.1 2-Chloro-5-methyl-4-phenylpyrimidine

0.57 g of 2-chloro-5-methyl-4-phenylpyrimidine was obtained in analogyto Example 24.1 from 1.00 g (6.13 mmol) of2,4-dichloro-5-methylpyrimidine.

¹H NMR (400 MHz, CDCl₃) δ (ppm: 8.47 (1H, s), 7.57 (2H, m), 7.47 (3H,m).

26.2 5-Methyl-4-phenylpyrimidin-2-ol

A 100% yield of 5-methyl-4-phenylpyrimidin-2-ol was obtained in analogyto Example 24.2 from 0.57 g (2.79 mmol) of2-chloro-5-methyl-4-phenylpyrimidine from Example 26.1.

ESI-MS: [M+H⁺]=187.15;

26.3 1-(4-Chlorobutyl)-5-methyl-4-phenylpyrimidin-2(1H)-one

0.29 g of 1-(4-chlorobutyl)-5-methyl-4-phenylpyrimidin-2(1H)-one wasobtained in analogy to Example 24.3 from 0.52 g (2.79 mmol) of5-methyl-4-phenylpyrimidin-2-ol from Example 26.2.

¹H NMR (500 MHz, CDCl₃) δ (ppm: 7.60 (2H, d), 7.46 (1H, s), 7.41 (3H,m), 3.96 (2H, t), 3.60 (2H, t), 2.14 (2H, t), 2.01 (2H, quint.), 1.89(2H, quint.).

26.41-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-5-methyl-4-phenylpyrimidin-2(1H)-one

0.14 g of the title compound was obtained in analogy to Example 5.2.2from 0.29 g (1.05 mmol) of1-(4-chlorobutyl)-5-methyl-4-phenylpyrimidin-2(1H)-one from Example26.3.

¹H NMR (500 MHz, CDCl₃) δ (ppm: 7.61 (2H, d), 7.49-7.41 (3H, m), 6.58(1H, s), 3.98 (2H, t), 3.70 (4H, s br.), 2.52 (4H, t), 2.43 (2H, t),2.14 (3H, s), 1.89 (2H, quint.), 1.63 (2H, quint.), 1.37 (9H, s).

Example 271-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-3-methylpyrimidine-2,4(1H,3H)-dione27.1 1-(4-Chlorobutyl)-3-methylpyrimidine-2,4(1H,3H)-dione

0.31 g of 1-(4-chlorobutyl)-3-methylpyrimidine-2,4(1H,3H)-dione wasobtained as a colorless oil in analogy to Example 25.1 from 0.50 g (2.47mmol) of 1-(4-chlorobutyl)-4-hydroxypyrimidin-2(1H)-one (obtainable inanalogy to the preparation of1-(4-bromobutyl)pyrimidine-2,4(1H,3H)-dione (see Example 13).

ESI-MS: [M+H⁺]=217.15.

27.21-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-3-methylpyrimidine-2,4(1H,3H)-dione

0.14 g of the title compound was obtained in analogy to Example 5.2.2from 0.31 g (1.43 mmol) of1-(4-chlorobutyl)-3-methylpyrimidine-2,4(1H,3H)-dione from Example 27.1.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.13 (1H, d), 6.56 (1H, s), 5.76 (1H,d), 3.79 (2H, t), 3.70 (4H, s br.), 3.33 (3H, s), 2.51 (4H, t), 2.43(2H, t), 1.78 (2H, quint.), 1.58 (2H, quint.), 1.34 (9H, s).

Example 281-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)pyrimidin-2(1H)-one

Preparation took place in the manner described in Example 14.

Example 291-{4-[4-(2-tert-Butyl-6-methylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-hydroxy-5-methylpyrimidin-2(1H)-one

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one (3.80 mmol, 0.82g) with 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine; yield0.40 g.

ESI-MS: 416.5, [M+H⁺]=415.5;

¹H NMR (500 MHz, CDCl₃) δ (ppm): 9.19 (1H, s br.), 6.97 (1H, s), 6.13(1H, s), 3.73 (2H, t), 3.63 (4H, m br.), 2.51 (4H, m), 2.42 (2H, t),2.35 (3H, s), 1.92 (3H, s), 1.74 (2H, quint.), 1.56 (2H, quint.), 1.33(9H, s).

Example 304-Hydroxy-5-methyl-1-{4-[4-(5,6,7,8-tetrahydronaphthalen-1-yl)piperazin-1-yl]butyl}pyrimidin-2(1H)-one

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one (5.00 mmol, 1.08g) with 4-(piperazin-1-yl)-5,6,7,8-tetrahydronaphthalene; yield 0.34 g.

ESI-MS: 398.4, [M+H⁺]=397.4, 199.3;

¹H NMR (500 MHz, CDCl₃) δ (ppm): 9.07 (1H, s br.), 7.08 (1H, t), 7.00(1H, s), 6.87 (1H, d), 6.82 (1H, d), 3.75 (2H, t), 2.95 (4H, s), 2.79(2H, m), 2.71 (2H, m), 2.63 (4H, s br.), 2.47 (2H, t), 1.94 (3H, s),1.76 (2H, quint.), 1.59 (2H, quint.).

Example 311-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}butyl)-4,6-dimethylpyrimidin-2(1H)-one

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-bromobutyl)-4,6-dimethylpyrimidin-2(1H)-one (1.54 mmol, 0.40 g,prepared from 4,6-dimethyl-2-hydroxypyrimidine in analogy to J. Am.Chem. Soc. 1993, 115, 7643 via4,6-dimethyl-2-[(trimethylsilyl)oxy]pyrimidine) with2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine.

ESI-MS: 290.3, [M+H⁺]=289.2, 165.6;

Example 32 1-[4-(4-tert-Butyl-2-oxopyrimidin-1(2H)-yl)butyl]-4-(2,6-di-tert-butylpyrimidin-4-yl)piperazin-1-iumchloride

The title compound was obtained in analogy to Example 5.2.2 by reacting4-tert-butyl-1-(4-chlorobutyl)pyrimidin-2(1H)-one (2.50 mmol, 0.61 g,see Example 14.1) with 2,6-di-tert-butyl-4-(piperazin-1-yl)pyrimidine;yield 0.29 g.

ESI-MS: 484.4, [M+H⁺]=483.4, 242.3;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.52 (1H, d), 6.37 (1H, d), 6.26 (1H,s), 3.93 (2H, t), 3.64 (4H, m), 2.50 (4H, m), 2.40 (2H, t), 1.83 (2H,quint.), 1.56 (2H, quint.), 1.39-1.17 (27H, m).

Example 331-{4-[4-(2,6-di-tert-Butylpyrimidin-4-yl)piperazin-1-yl]butyl}pyrimidine-2,4(1H,3H)-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-bromobutyl)pyrimidine-2,4(1H,3H)-dione (2.50 mmol, 0.51 g) with2,6-di-tert-butyl-4-(piperazin-1-yl)pyrimidine; yield 0.45 g.

ESI-MS: 444.4, [M+H⁺]=443.2, 222.1;

¹H NMR (400 MHz, CDCl₃) δ (ppm: 8.86 (1H, s br.), 7.15 (1H, d), 6.25(1H, s), 5.68 (1H, d), 3.74 (2H, t), 3.63 (4H, m), 2.51 (4H, m), 2.40(2H, t), 1.75 (2H, quint.), 1.57 (2H, quint.), 1.33 (9H, s), 1.27 (9H,s).

Example 344-(2,6-di-tert-Butylpyrimidin-4-yl)-1-[4-(4-methyl-2-oxopyrimidin-1(2H)-yl)butyl]piperazin-1-ium chloride

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-methylpyrimidin-2(1H)-one (2.50 mmol, 0.50 g) with2,6-di-tert-butyl-4-(piperazin-1-yl)pyrimidine; yield 0.25 g.

ESI-MS: 442.3, [M+H⁺]=441.2, 221.1;

Example 354-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(4-methyl-2-oxopyrimidin-1(2H)-yl)butyl]piperazin-1-ium chloride

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-methylpyrimidin-2(1H)-one (2.50 mmol, 0.50 g) with2-tert-butyl-4-(piperazin-1-yl)-6-propylpyrimidine; yield 0.22 g.

¹H NMR (400 MHz, CDCl₃) δ (ppm: 7.48 (1H, d), 6.19 (1H, d), 6.12 (1H,s), 3.88 (2H, t), 3.60 (4H, m), 2.50 (2H, t), 2.47-2.42 (4H, m), 2.33(5H, m), 1.88-1.62 (4H, m), 1.55 (2H, quint.), 1.30 (9H, s), 0.94 (3H,t).

Example 361-((2E)-4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}-2-methylbut-2-en-1-yl)-5-methylpyrimidine-2,4(1H,3H)-dione

The title compound was obtained in analogy to Example 5.2.2 by reactingthymine (3.50 mmol, 0.44 g) with2-tert-butyl-4-{4-[(2E)-4-chloro-3-methylbut-2-en-1-yl]piperazin-1-yl}-6-trifluoromethylpyrimidine(3.50 mmol, 1.50 g, prepared as in DE 19735410); yield 0.78 g.

ESI-MS: 482.2, [M+H⁺]=481.2, 241.1;

Example 371-(4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}-2-methylbutyl)-5-methylpyrimidine-2,4(1H,3H)-dione

1-((2E)-4-{4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}-2-methylbut-2-en-1-yl)-5-methylpyrimidine-2,4(1H,3H)-dione(Example 36, 1.04 mmol, 0.50 g) in methanol (5 ml) was hydrogenated overPd (10% on activated carbon) with hydrogen at room temperature for 12 hand then at 40° C. for a further 6 h. The mixture was filtered and theresidue was washed with methanol. The filtrate was concentrated andpurified on silica gel (mobile phase: dichloromethane/methanol: 97/3v/v); yield 0.20 g.

ESI-MS: 484.2, [M+H⁺]=483.3, 242.1;

Example 384-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[1-methyl-4-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)butyl]piperazin-1-ium chloride

The title compound was obtained in analogy to Example 5.2.2. by reacting1-(4-bromopentyl)-5-methylpyrimidine-2,4(1H,3H)-dione (0.47 mmol, 0.13g, prepared in analogy to Example 6.2 from thymine and1,4-dibromopentane) with2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine; yield 0.03 g.

ESI-MS: 458.5, [M+H⁺]=457.5, 229.3;

Example 394-(2-tert-Butyl-6-isopropylpyrimidin-4-yl)-1-[4-(4-methyl-2-oxopyrimidin-1(2H)-yl)butyl]piperazin-1-ium chloride

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-methylpyrimidin-2(1H)-one (1.25 mmol, 0.25 g) with2-tert-butyl-4-(piperazin-1-yl)-6-isopropylpyrimidine; yield 0.04 g.

ESI-MS: [M+H⁺]=427.5, 214.2, 143.2

Example 404-(2-tert-Butyl-6-isopropylpyrimidin-4-yl)-1-[4-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-butyl]piperazin-1-iumchloride

0.22 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione (1.00 mmol,0.22 g) with 2-tert-butyl-4-isopropyl-6-piperazin-1-ylpyrimidine (0.95mmol, 0.25 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=443.5, 222.4.

Example 411-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-trifluoromethyl-1H-pyrimidin-2-one

0.21 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-trifluoromethyl-1H-pyrimidin-2-one fromExample 15.1 (0.98 mmol, 0.25 g) with2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.98 mmol, 0.26 g;prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=481.4, 241.1.

Example 421-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-3-methyl-1H-pyrimidine-2,4-dione(BSF 4105765, 1044-138)

0.19 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-3-methyl-1H-pyrimidine-2,4-dione from Example27.1 (0.92 mmol, 0.20 g) with2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.92 mmol, 0.24 g;prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=443.4, 222.2.

Example 434-(4-Fluorophenyl)-1-[4-(4-methylpiperazin-1-yl)butyl]-1H-pyrimidin-2-one43.1 2-Chloro-4-(4-fluorophenyl)pyrimidine

6.73 g of 2-chloro-4-(4-fluorophenyl)pyrimidine were obtained in analogyto Example 24.1 from 2,4-dichloropyrimidine (40.00 mmol, 5.96 g) and4-fluorophenylboronic acid (40.00 mmol, 5.60 g).

43.2 4-(4-Fluorophenyl)pyrimidin-2-ol

6.27 g of 4-(4-fluorophenyl)pyrimidin-2-ol were obtained in analogy toExample 24.2 from 2-chloro-4-(4-fluorophenyl)pyrimidine from Example43.1 (32.26 mmol, 6.73 g).

ESI-MS: [M+K⁺]=228.9, [M+H⁺]=191.1.

43.3 1-(4-Chlorobutyl)-4-(4-fluorophenyl)-1H-pyrimidin-2-one

1.00 g of 1-(4-chlorobutyl)-4-(4-fluorophenyl)-1H-pyrimidin-2-one wasobtained in analogy to Example 24.3 by reacting4-(4-fluorophenyl)pyrimidin-2-ol from Example 43.2 (15.77 mmol, 3.00 g)with 1-bromo-4-chlorobutane.

ESI-MS: 321.0, [M+K⁺]=319.0, 283.0, [M+H⁺]=281.0.

43.44-(4-Fluorophenyl)-1-[4-(4-methylpiperazin-1-yl)butyl]-1H-pyrimidin-2-one

0.08 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-(4-fluorophenyl)-1H-pyrimidin-2-one fromExample 43.3 (0.61 mmol, 0.17 g) with 1-methylpiperazine (0.57 mmol,0.06 g).

ESI-MS: 346.1, [M+H⁺]=345.2, 173.1.

Example 441-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-(4-fluorophenyl)-1H-pyrimidin-2-one

0.29 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-(4-fluorophenyl)-1H-pyrimidin-2-one fromExample 43.3 (0.61 mmol, 0.17 g) with2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.74 mmol, 0.20 g;prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=507.4, 254.1.

Example 454-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-{4-[4-(4-fluorophenyl)-2-oxo-2H-pyrimidin-1-yl]butyl}piperazin-1-iumchloride

0.13 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-(4-fluorophenyl)-1H-pyrimidin-2-one fromExample 43.3 (0.40 mmol, 0.11 g) with2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.38 mmol,0.11 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=533.3, 267.1.

Example 461-(2E)-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]-2-methylbut-2-enyl}-1H-pyrimidine-2,4-dione

0.14 g of the title compound was obtained in analogy to Example 5.2.2 byreacting uracil (0.60 mmol, 0.07 g) with4-(2-tert-butyl-6-trifluoromethylpyrimidin-4-yl)-1-(4-chloro-3-methylbut-2-enyl)piperazin-1-iumchloride (0.60 mmol, 0.26 g, prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=467.3, 234.1;

Example 471-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile

27.0 mg of the title compound were obtained in analogy to Example 5.2.2by reacting1-(4-chlorobutyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrilefrom Example 18.1 (0.31 mmol, 0.07 g) with2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.31 mmol, 0.08 g;prepared as described in DE 19735410).

ESI-MS: 455.3, [M+H⁺]=454.2, 227.6.

Example 484-Azetidin-1-yl-1-{4-[4-(2-tert-butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidin-2-one

A mixture of1-{4-[4-(2-tert-butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-5-methyl-4-thioxo-3,4-dihydro-1H-pyrimidin-2-onefrom Example 2 (0.24 mmol, 0.12 g) and azetidine (5.81 mmol, 0.33 g) inethanol (1.9 ml) was stirred at 60° C. in a microwave (Milestone Ethos1600) for 1 hour. The reaction mixture was then concentrated and theresulting residue was purified by column chromatography on silica gel(eluent: CH₂Cl₂/methanol 95/5), resulting in 0.08 g of the titlecompound.

ESI-MS: 509.2, [M+H⁺]=508.3, 254.6.

Example 491-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-phenyl-1H-pyrimidin-2-one

0.30 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-phenylpyrimidin-2(1H)-one from Example 24.3(1.13 mmol, 0.3 g) with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine(1.13 mmol, 0.3 g; prepared as described in DE 19735410).

ESI-MS: 490.4, 489.4, 245.1.

Example 501-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-furan-2-yl-1H-pyrimidin-2-one50.1 2-Chloro-4-furan-2-ylpyrimidine

3.87 g of 2-chloro-4-furan-2-ylpyrimidine were obtained in analogy toExample 24.1 by reacting 2,4-dichloropyrimidine (33.56 mmol, 5.00 g)with furan-2-boronic acid (33.56 mmol, 3.76 g).

ESI-MS: 183.1, [M+H⁺]=181.1.

50.2 4-Furan-2-ylpyrimidin-2-ol

4.16 g of 4-furan-2-ylpyrimidin-2-ol were obtained in analogy to Example24.2 from 2-chloro-4-furan-2-ylpyrimidine from Example 50.1 (21.43 mmol,3.87 g).

ESI-MS: [2M+Na⁺]=347.0, [M+H⁺]=163.1.

50.3 1-(4-Chlorobutyl)-4-furan-2-yl-1H-pyrimidin-2-one

0.61 g of 1-(4-chlorobutyl)-4-furan-2-yl-1H-pyrimidin-2-one was obtainedin analogy to Example 24.3 from 4-furan-2-ylpyrimidin-2-ol from Example50.2 (12.83 mmol, 2.08 g).

ESI-MS: 255.1, [M+H⁺]=253.1.

50.41-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-furan-2-yl-1H-pyrimidin-2-one

0.14 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-furan-2-yl-1H-pyrimidin-2-one from Example50.3 (1.19 mmol, 0.30 g) with2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (1.19 mmol, 0.31 g;prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=479.4, 240.1.

Example 511-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-furan-2-yl-1H-pyrimidin-2-one

0.29 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-furan-2-yl-1H-pyrimidin-2-one from Example50.3 (1.19 mmol, 0.30 g) with2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (1.18 mmol,0.34 g; prepared as described in DE 19735410).

ESI-MS: 506.2, [M+H⁺]=505.2, 253.1.

Example 521-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-5-chloro-1H-pyrimidine-2,4-dione52.1 5-Chloro-1-(4-chlorobutyl)-1H-pyrimidine-2,4-dione

1.75 g of the title compound were obtained in analogy to Example 18.1from 5-chlorouracil (34.12 mmol, 5.00 g) and 1-bromo-4-chlorobutane.

ESI-MS: 239.1, [M+H⁺]=237.1.

52.21-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-5-chloro-1H-pyrimidine-2,4-dione

0.10 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 5-chloro-1-(4-chlorobutyl)-1H-pyrimidine-2,4-dione from Example52.1 (0.84 mmol, 0.20 g) with2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.85 mmol,0.25 g; prepared as described in DE 19735410).

ESI-MS: 492.3, [M+H⁺]=489.2, 245.1.

Example 531-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-5-fluoro-1H-pyrimidine-2,4-dione

0.50 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-5-fluoro-1H-pyrimidine-2,4-dione from Example16.1 (2.27 mmol, 0.50 g) with2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (2.27 mmol, 0.60 g;prepared as described in DE 19735410).

¹H NMR (400 MHz, DMSO-d₆) δ (ppm: 8.08 (1H, d), 6.41 (1H, s), 3.63 (2H,t), 3.56 (4H, s br.), 2.46 (2H, t), 2.38 (4H, s br.), 2.30 (2H, t), 1.60(4H, m), 1.43 (2H, m), 1.24 (9H, s), 0.89 (3H, t).

Example 541-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]pentyl}-5-methyl-1H-pyrimidine-2,4-dione

0.29 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-bromopentyl)-5-methyl-1H-pyrimidine-2,4-dione (1.82 mmol,0.50 g; prepared in analogy to Example 6.2 from thymine and1,4-dibromopentane) with2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (1.73 mmol,0.50 g; prepared as described in DE 19735410).

ESI-MS: 484.2, [M+H⁺]=483.3, 242.1.

Example 551-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-5-trifluoromethyl-1H-pyrimidine-2,4-dione55.1 1-(4-Chlorobutyl)-5-trifluoromethyl-1H-pyrimidine-2,4-dione

0.42 g of 1-(4-chlorobutyl)-5-trifluoromethyl-1H-pyrimidine-2,4-dionewas obtained in analogy to Example 18.1 by reacting5-trifluoromethyl-1H-pyrimidine-2,4-dione (5.28 mmol, 0.98 g) with1-bromo-4-chlorobutane.

ESI-MS: 311.0, [M+K⁺]=309.0, 273.0, [M+H⁺]=271.0.

55.21-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-5-trifluoromethyl-1H-pyrimidine-2,4-dione

75.0 mg of the title compound were obtained in analogy to Example 5.2.2by reacting 1-(4-chlorobutyl)-5-trifluoromethyl-1H-pyrimidine-2,4-dionefrom Example 55.1 (0.55 mmol, 0.15 g) with2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.53 mmol,0.15 g; prepared as described in DE 19735410).

ESI-MS: 524.3, [M+H⁺]=523.2, 262.1.

Example 561-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-5-trifluoromethyl-1H-pyrimidine-2,4-dione

40.0 mg of the title compound were obtained in analogy to Example 5.2.2by reacting 1-(4-chlorobutyl)-5-trifluoromethyl-1H-pyrimidine-2,4-dionefrom Example 55.1 (0.55 mmol, 0.15 g) with2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.53 mmol, 0.14 g;prepared as described in DE 19735410).

ESI-MS: 498.2, [M+H⁺]=497.2, 249.1.

Example 574-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(2-oxo-4-(o-tolyl)-2H-pyrimidin-1-yl)butyl]-piperazin-1-iumfumarate 57.1 2-Chloro-4-(o-tolyl)pyrimidine

3.10 g of 2-chloro-4-(o-tolyl)pyrimidine were obtained in analogy toExample 24.1 from 2,4-dichloropyrimidine (13.42 mmol, 2.00 g) ando-tolueneboronic acid (13.42 mmol, 1.83 g).

57.2 4-(o-Tolyl)-1H-pyrimidin-2-one

50.0 mg of 4-(o-tolyl)-1H-pyrimidin-2-one were obtained in analogy toExample 24.2 by use of 2-chloro-4-(o-tolyl)pyrimidine from Example 57.1(0.49 mmol, 0.10 g).

ESI-MS: [M+H⁺]=187.1.

57.3 1-(4-Chlorobutyl)-4-(o-tolyl)-1H-pyrimidin-2-one

1.54 g of 1-(4-chlorobutyl)-4-(o-tolyl)-1H-pyrimidin-2-one were obtainedin analogy to Example 24.3 by reacting 4-(o-tolyl)-1H-pyrimidin-2-one(7.30 mmol, 1.36 g) with 1-bromo-4-chlorobutane.

ESI-MS: 279.0, [M+H⁺]=277.0.

57.44-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(2-oxo-4-(o-tolyl)-2H-pyrimidin-1-yl)butyl]piperazin-1-iumfumarate

0.15 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-(o-tolyl)-1H-pyrimidin-2-one from Example57.3 (0.72 mmol, 0.20 g) with2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.69 mmol, 0.18 g;prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=503.4, 252.1.

Example 581-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-(m-tolyl)-1H-pyrimidin-2-one58.1 2-Chloro-4-(m-tolyl)pyrimidine

4.70 g of 2-chloro-4-(m-tolyl)pyrimidine were obtained in analogy toExample 24.1 by reacting 2,4-dichloropyrimidine (20.14 mmol, 3.00 g)with 4-m-tolylboronic acid (20.14 mmol, 2.74 g).

58.2 4-(m-Tolyl)-1H-pyrimidin-2-one

1.34 g of 4-(m-tolyl)-1H-pyrimidin-2-one were obtained in analogy toExample 24.2 starting from 2-chloro-4-(m-tolyl)pyrimidine from Example58.1 (14.66 mmol, 3.00 g).

ESI-MS: [M+H⁺]=187.1.

58.3 1-(4-Chlorobutyl)-4-(m-tolyl)-1H-pyrimidin-2-one

1.17 g of the title compound were obtained in analogy to Example 24.3 byreacting 4-(m-tolyl)-1H-pyrimidin-2-one (6.98 mmol, 1.30 g) with1-bromo-4-chlorobutane.

ESI-MS: 279.0, [M+H⁺]=277.0;

58.41-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-(m-tolyl)-1H-pyrimidin-2-one

0.12 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-(m-tolyl)-1H-pyrimidin-2-one from Example58.3 (0.54 mmol, 0.15 g) with2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.40 mmol,0.14 g; prepared as described in DE 19735410).

ESI-MS: 530.3, [M+H⁺]=529.3, 265.1.

Example 591-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-(m-tolyl)-1H-pyrimidin-2-one

0.15 g of1-{4-[4-(2-tert-butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-(m-tolyl)-1H-pyrimidin-2-onewas obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-(m-tolyl)-1H-pyrimidin-2-one from Example 58.3 (0.54mmol, 0.15 g) with 2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine(0.49 mmol, 0.13 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=503.4, 252.2.

Example 604-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(2-oxo-4-(o-tolyl)-2H-pyrimidin-1-yl)butyl]piperazin-1-iumfumarate

0.21 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-(o-tolyl)-1H-pyrimidin-2-one from Example57.3 (0.72 mmol, 0.20 g) with2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.69 mmol,0.20 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=529.3, 265.1.

Example 614-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-1-methylbutyl]piperazin-1-iumfumarate 61.1 1-(4-Bromopentyl)-1H-pyrimidine-2,4-dione

1.07 g of the title compound were obtained in analogy to Example 6.2 byreacting uracil (28.55 mmol, 3.20 g) with 1,4-dibromopentane (29.35mmol, 6.75 g).

ESI-MS: 263.0, [M+H⁺]=261.0.

61.24-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-1-methylbutyl]piperazin-1-iumfumarate

0.10 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-bromopentyl)-1H-pyrimidine-2,4-dione from Example 61.1(1.15 mmol, 0.30 g) with2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (1.09 mmol, 0.29 g;prepared as described in DE 19735410).

ESI-MS: 444.4, [M+H⁺]=443.4, 222.1.

Example 621-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]pentyl}-1H-pyrimidine-2,4-dione

0.07 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-bromopentyl)-1H-pyrimidine-2,4-dione from Example 61.1(1.15 mmol, 0.30 g) with2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (1.09 mmol,0.31 g; prepared as described in DE 19735410).

ESI-MS: 470.2, [M+H⁺]=469.2, 235.1.

Example 63(+)-1-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]pentyl}-5-methyl-1H-pyrimidine-2,4-dione

For racemate resolution, a solution of4-(2-tert-butyl-6-propylpyrimidin-4-yl)-1-[1-methyl-4-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)butyl]piperazin-1-ium chloride from Example 38 (200 mg) in 3 mlof hexane/isopropanol (9:1 (V/V)) was loaded onto a chiral column(DAICEL ChiralPAK AD, length: 50 cm, internal diameter: 5 cm, particlesize: 20μ); eluent: hexane/ethanol/triethylamine (85:15:0.1 (V/V)). 0.08g of the title compound was obtained after concentration of theresulting filtrate.

ESI-MS: 458.4, [M+H⁺]=457.4, 229.1;

α (20° C., c=2 mg/ml, CHCl₃, I=1 dm): +10°.

Example 64(−)-1-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]-2-methylbutyl}-5-methyl-1H-pyrimidine-2,4-dione

For racemate resolution, a solution of1-(4-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}-2-methylbutyl)-5-methylpyrimidine-2,4(1H,3H)-dione(200 mg) from Example 37 in 3 ml of hexane/isopropanol (9:1 (V/V)) wasloaded onto an optical column (DAICEL ChiralPAK AD, length: 50 cm,internal diameter: 5 cm, particle size: 20μ, eluent:hexane/ethanol/triethylamine (85:15:0, 1 (V/V)). 0.08 g of the titlecompound was obtained after concentration of the resulting filtrate.

ESI-MS: [M+H⁺]=483.3, 242.1;

α (20° C., c=2 mg/ml, CHCl₃, I=1 dm): −25.5°.

Example 651-(2E)-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]-2-methylbut-2-enyl}-5-methyl-1H-pyrimidine-2,4-dione

0.16 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 5-methyl-1H-pyrimidine-2,4-dione (0.60 mmol, 0.08 g) and4-(2-tert-butyl-6-trifluoromethylpyrimidin-4-yl)-1-(4-chloro-3-methylbut-2-enyl)piperazin-1-iumchloride (0.60 mmol, 0.22 g; prepared as described in DE 19735410).

ESI-MS: 456.4, [M+H⁺]=455.4, 228.1.

Example 664-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(2-oxo-4-(p-tolyl)-2H-pyrimidin-1-yl)butyl]piperazin-1-iumfumarate 66.1 2-Chloro-4-(p-tolyl)pyrimidine

3.19 g of 2-chloro-4-(p-tolyl)pyrimidine were obtained in analogy toExample 24.1 by reacting 2,4-dichloropyrimidine (13.42 mmol, 2.00 g)with p-tolylboronic acid (13.42 mmol, 1.83 g).

66.2 4-(p-Tolyl)-1H-pyrimidin-2-one

1.95 g of the title compound were obtained in analogy to Example 24.2from 2-chloro-4-(p-tolyl)pyrimidine (15.59 mmol, 3.19 g) from Example66.1.

ESI-MS: [M+H⁺]=187.1.

66.3 1-(4-Chlorobutyl)-4-(p-tolyl)-1H-pyrimidin-2-one

2.47 g of 1-(4-chlorobutyl)-4-(p-tolyl)-1H-pyrimidin-2-one were obtainedin analogy to Example 24.3 by reacting 4-(p-tolyl)-1H-pyrimidin-2-onefrom Example 66.2 (10.47 mmol, 1.95 g) with 1-bromo-4-chlorobutane.

ESI-MS: 279.1, [M+H⁺]=277.0.

66.44-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(2-oxo-4-(p-tolyl)-2H-pyrimidin-1-yl)butyl]piperazin-1-iumfumarate

0.27 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-(p-tolyl)-1H-pyrimidin-2-one from Example66.3 (0.90 mmol, 0.25 g) with2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.81 mmol,0.23 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=529.3, 265.1.

Example 674-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-{4-[4-(2-fluorophenyl)-2-oxo-2H-pyrimidin-1-yl]butyl}piperazin-1-iumfumarate 67.1 2-Chloro-4-(2-fluorophenyl)pyrimidine

1.10 g of 2-chloro-4-(2-fluorophenyl)pyrimidine were obtained in analogyto Example 24.1 by reacting 2,4-dichloropyrimidine (13.42 mmol, 2.00 g)with 2-fluorophenylboronic acid (13.42 mmol, 1.88 g).

ESI-MS: 211.1, [M+H⁺]=209.1.

67.2 4-(2-Fluorophenyl)pyrimidin-2-ol

1.10 g of 4-(2-fluorophenyl)pyrimidin-2-ol were obtained in analogy toExample 24.2 from 2-chloro-4-(2-fluorophenyl)pyrimidine from Example67.1 (5.27 mmol, 1.10 g).

ESI-MS: [M+H⁺]=191.1.

67.3 1-(4-Chlorobutyl)-4-(2-fluorophenyl)-1H-pyrimidin-2-one

0.48 g of the title compound was obtained in analogy to Example 24.3 byreacting 4-(2-fluorophenyl)pyrimidin-2-ol (5.52 mmol, 1.05 g) fromExample 67.2 with 1-bromo-4-chlorobutane.

67.44-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-{4-[4-(2-fluorophenyl)-2-oxo-2H-pyrimidin-1-yl]butyl}piperazin-1-iumfumarate

0.33 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-(2-fluorophenyl)-1H-pyrimidin-2-one fromExample 67.3 (0.61 mmol, 0.20 g) with2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.64 mmol,0.18 g; prepared as described in DE 19735410).

ESI-MS: 534.2, [M+H⁺]=533.3, 267.1.

Example 68(+)-1-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]-2-methylbutyl}-5-methyl-1H-pyrimidine-2,4-dione

For racemate resolution, a solution of1-(4-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}-2-methylbutyl)-5-methylpyrimidine-2,4(1H,3H)-dionefrom Example 37 (200 mg) in 1.5 ml of isopropanol, 1.5 ml of hexane and80 μl of methanol was loaded onto a chiral column (DAICEL ChiralPAK AD,length: 50 cm, internal diameter: 5 cm, particle size: 20μ); eluent:hexane/ethanol/triethylamine (85:15:0.1 (V/V)). 0.08 g of the titlecompound was obtained after concentration of the resulting filtrate.

ESI-MS: [M+H⁺]=483.3, 242.1;

α (20° C., c=2 mg/ml, CHCl₃, I=1 dm): +17°.

Example 691-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-methyl-1H-pyrimidin-2-one

0.23 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-(2-fluorophenyl)-1H-pyrimidin-2-one fromExample 67.3 (0.61 mmol, 0.20 g) with2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.64 mmol, 0.17 g;prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=507.4, 254.1.

Example 701-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]-2-methylbutyl}-5-methyl-1H-pyrimidine-2,4-dione

7.5 mg of the title compound were obtained in analogy to Example 37 from1-{4-[4-(2-tert-butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]-2-methylbut-2-enyl}-5-methyl-1H-pyrimidine-2,4-dionefrom Example 65 (0.06 mmol, 25.0 mg).

ESI-MS: 458.4, [M+H⁺]=457.4, 229.1.

Example 711-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-cyclobutyl-1H-pyrimidin-2-one71.1 1-Cyclobutyl-3,3-dimethoxypropan-1-one

11.00 g of the title compound were obtained in analogy to Helv. Chim.Acta 2002, 85, 2926-29 (Example 6, p. 2928) by reacting1-cyclobutylethanone (152.83 mmol, 15.00 g) with methyl formate (308.16mmol, 18.51 g).

71.2 4-Cyclobutyl-1H-pyrimidin-2-one

0.75 g of 4-cyclobutyl-1H-pyrimidin-2-one was obtained in analogy toExample 8.1 by reacting 1-cyclobutyl-3,3-dimethoxypropan-1-one (63.87mmol, 11.00 g) from Example 71.1 with urea.

71.3 1-(4-Chlorobutyl)-4-cyclobutyl-1H-pyrimidin-2-one

0.38 g of the title compound was obtained in analogy to Example 5.2.1 byreacting 4-cyclobutyl-1H-pyrimidin-2-one from Example 71.2 (4.99 mmol,0.75 g) with 1-bromo-4-chlorobutane.

ESI-MS: 243.1 [M+H⁺]=241.1.

71.41-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-cyclobutyl-1H-pyrimidin-2-one

0.19 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-cyclobutyl-1H-pyrimidin-2-one from Example71.3 (0.75 mmol, 0.18 g) with2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.67 mmol,0.19 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=493.4, 247.1.

Example 724-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-{4-[4-(3-fluorophenyl)-2-oxo-2H-pyrimidin-1-yl]butyl}piperazin-1-iumfumarate 72.1 2-Chloro-4-(3-fluorophenyl)pyrimidine

1.00 g of 2-chloro-4-(3-fluorophenyl)pyrimidine was obtained in analogyto Example 24.1 by reacting 2,4-dichloropyrimidine (13.42 mmol, 2.00 g)with 3-fluorophenylboronic acid (13.42 mmol, 1.88 g).

ESI-MS: 210.9, [M+H⁺]=208.9.

72.2 4-(3-Fluorophenyl)pyrimidin-2-ol

1.06 g of 4-(3-fluorophenyl)pyrimidin-2-ol were obtained in analogy toExample 24.2 from 2-chloro-4-(3-fluorophenyl)pyrimidine from Example72.1 (4.79 mmol, 1.00 g).

ESI-MS: [M+H⁺]=191.1.

72.3 1-(4-Chlorobutyl)-4-(3-fluorophenyl)-1H-pyrimidin-2-one

0.34 g of the title compound was obtained in analogy to Example 24.3 byreacting 4-(3-fluorophenyl)pyrimidin-2-ol from Example 72.2 (5.26 mmol,1.00 g) with 1-bromo-4-chlorobutane.

ESI-MS: 283.0, [M+H⁺]=281.0.

72.44-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-{4-[4-(3-fluorophenyl)-2-oxo-2H-pyrimidin-1-yl]butyl}piperazin-1-iumfumarate

0.11 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-(3-fluorophenyl)-1H-pyrimidin-2-one fromExample 72.3 (0.61 mmol, 0.17 g) with2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.55 mmol, 0.14 g;prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=507.4, 254.2.

Example 734-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-{4-[4-(3-fluorophenyl)-2-oxo-2H-pyrimidin-1-yl]butyl}piperazin-1-iumfumarate

0.16 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-(3-fluorophenyl)-1H-pyrimidin-2-one fromExample 72.3 (0.61 mmol, 0.17 g) with2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.55 mmol,0.16 g; prepared as described in DE 19735410).

ESI-MS: [M+Na⁺]=555.3, 534.3, [M+H⁺]=533.3, 267.3.

Example 741-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-cyclobutyl-1H-pyrimidin-2-one

0.12 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-cyclobutyl-1H-pyrimidin-2-one from Example71.3 (0.75 mmol, 0.18 g) with2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.67 mmol, 0.18 g;prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=467.4, 234.1.

Example 754-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(2-oxo-4-(p-tolyl)-2H-pyrimidin-1-yl)butyl]piperazine1-fumarate

0.18 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-(p-tolyl)-1H-pyrimidin-2-one from Example66.3 (0.90 mmol, 0.25 g) with2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.81 mmol, 0.21 g;prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=503.4, 252.1.

Example 76(−)-1-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]pentyl}-5-methyl-1H-pyrimidine-2,4-dione

For racemate resolution, a solution of4-(2-tert-butyl-6-propylpyrimidin-4-yl)-1-[1-methyl-4-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)butyl]piperazin-1-ium chloride from Example 38 (200 mg) in 3 mlof hexane/isopropanol (9:1 (V/V)) was loaded onto a chiral column(DAICEL ChiralPAK AD, length: 50 cm, internal diameter: 5 cm, particlesize: 20μ); eluent: hexane/ethanol/triethylamine (85:15:0.1 (V/V)). 0.08g of the title compound was obtained after concentration of theresulting filtrate.

ESI-MS: 458.4, [M+H⁺]=457.4, 229.1;

α (20° C., c=2 mg/ml, CHCl₃, I=1 dm): −22°.

Example 774-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(5-chloro-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)butyl]piperazin-1-iumacetate

65.0 mg of the title compound were obtained in analogy to Example 5.2.2by reacting 5-chloro-1-(4-chlorobutyl)-1H-pyrimidine-2,4-dione fromExample 52.1 (0.83 mmol, 0.20 g) with2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.86 mmol, 0.23 g;prepared as described in DE 19735410).

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.16 (1H, s), 6.43 (1H, s), 3.69 (2H,t), 3.57 (4H, s br.), 2.46 (2H, t), 2.39 (4H, s br.), 2.30 (2H, t), 1.64(4H, m), 1.44 (2H, quint.), 1.27 (9H, s), 0.88 (3H, t).

Example 781-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butyl}-1H-pyrimidine-2,4-dione

0.21 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-1H-pyrimidine-2,4-dione (prepared asdescribed in J. Am. Chem. Soc. 1993, 115, 7636) (0.74 mmol, 0.15 g) with1-(2,3-dichlorophenyl)piperazine (0.66 mmol, 0.15 g).

ESI-MS: 399.0, [M+H⁺]=397.0.

Example 791-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butyl}-5-fluoro-1H-pyrimidine-2,4-dione

0.21 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-5-fluoro-1H-pyrimidine-2,4-dione from Example16.1 (0.91 mmol, 0.20 g) with 1-(2,3-dichlorophenyl)piperazine (0.82mmol, 0.19 g).

ESI-MS: 417.3, [M+H⁺]=415.3.

Example 801-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butyl}-4-methyl-1H-pyrimidin-2-one

70.0 mg of the title compound were obtained in analogy to Example 5.2.2by reacting 1-(4-chlorobutyl)-4-methyl-1H-pyrimidin-2-one from Example8.2 (0.37 mmol, 75.0 mg) with 1-(2,3-dichlorophenyl)piperazine (0.34mmol, 77.73 mg).

ESI-MS: 397.1, 395.1.

Example 814-(2,3-Dichlorophenyl)-1-[4-(2-oxo-4-phenyl-2H-pyrimidin-1-yl)butyl]piperazin-1-iumfumarate

0.16 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-phenyl-1H-pyrimidin-2-one from Example 24.3(0.76 mmol, 0.20 g) with 1-(2,3-dichlorophenyl)piperazine (0.69 mmol,0.16 g).

ESI-MS: 459.0, [M+H⁺]=458.1, 457.1, 229.1.

Example 821-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

0.17 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione from Example5.2.1 (0.69 mmol, 0.15 g) with 1-(2,3-dichlorophenyl)piperazine (0.62mmol, 0.14 g).

ESI-MS: 427.15, 425.15.

Example 834-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(5-ethyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)butyl]piperazine1-fumarate 83.1 1-(4-Chlorobutyl)-5-ethyl-1H-pyrimidine-2,4-dione

0.21 g of 1-(4-chlorobutyl)-5-ethyl-1H-pyrimidine-2,4-dione was obtainedin analogy to Example 18.1 by reacting 5-ethyl-1H-pyrimidine-2,4-dione(6.42 mmol, 0.90 g) with 1-bromo-4-chlorobutane.

ESI-MS: 233.1, [M+H⁺]=231.1.

83.24-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(5-ethyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)butyl]piperazine1-fumarate

0.14 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-5-ethyl-1H-pyrimidine-2,4-dione from Example83.1 (0.35 mmol, 0.08 g) with2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.36 mmol,0.11 g; prepared as described in DE 19735410).

ESI-MS: 484.2, [M+H⁺]=483.3, 242.1.

Example 844-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(5-ethyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)butyl]piperazin-1-iumfumarate

0.07 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-5-ethyl-1H-pyrimidine-2,4-dione from Example83.1 (0.35 mmol, 0.08 g) with2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.36 mmol, 0.10 g;prepared as described in DE 19735410).

ESI-MS: 458.4, [M+H⁺]=457.4, 229.1.

Example 854-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(4-ethoxy-2-oxo-2H-pyrimidin-1-yl)butyl]piperazin-1-iumfumarate 85.1 1-(4-Chlorobutyl)-4-ethoxy-1H-pyrimidin-2-one

0.21 g of 1-(4-chlorobutyl)-4-ethoxy-1H-pyrimidin-2-one was obtained inanalogy to Example 5.2.1 by reacting 4-ethoxy-1H-pyrimidin-2-one (4.17mmol, 0.59 g) with 1-bromo-4-chlorobutane.

ESI-MS: [M+K⁺]=269.0, 233.1, 232.1, [M+H⁺]=231.1.

85.24-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(4-ethoxy-2-oxo-2H-pyrimidin-1-yl)butyl]piperazin-1-iumfumarate

0.13 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-ethoxy-1H-pyrimidin-2-one from Example 85.1(0.56 mmol, 0.13 g) with2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.57 mmol,0.17 g; prepared as described in DE 19735410).

ESI-MS: [M+K⁺]=521.3, [M+H⁺]=484.2, 483.3.

Example 864-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(4-ethoxy-2-oxo-2H-pyrimidin-1-yl)butyl]piperazin-1-iumfumarate

0.14 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-ethoxy-1H-pyrimidin-2-one from Example 85.1(0.56 mmol, 0.13 g) with2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.57 mmol, 0.15 g;prepared as described in DE 19735410).

ESI-MS: [M+Na⁺]=495.2, 459.4, 458.4, [M+H⁺]=457.4.

Example 871-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-thiophen-2-yl-1H-pyrimidin-2-one87.1 2-Chloro-4-thiophen-2-ylpyrimidine

5.16 g of 2-chloro-4-thiophen-2-ylpyrimidine were obtained in analogy toExample 24.1 by reacting 2,4-dichloropyrimidine (33.56 mmol, 5.00 g)with thiophene-2-boronic acid (33.56 mmol, 4.29 g).

ESI-MS: 198.9, [M+H⁺]=196.9.

87.2 4-Thiophen-2-ylpyrimidin-2-ol

5.40 g of 4-thiophen-2-ylpyrimidin-2-ol were obtained in analogy toExample 24.2 from 2-chloro-4-thiophen-2-ylpyrimidine from Example 87.1(26.24 mmol, 5.16 g).

ESI-MS: [M+H⁺]=179.1.

87.3 1-(4-Chlorobutyl)-4-thiophen-2-yl-1H-pyrimidin-2-one

4.48 g of 1-(4-chlorobutyl)-4-thiophen-2-yl-1H-pyrimidin-2-one wereobtained in analogy to Example 24.3 by reacting4-thiophen-2-ylpyrimidin-2-ol from Example 87.2 (16.83 mmol, 3.00 g)with 1-bromo-4-chlorobutane.

ESI-MS: 271.0, [M+H⁺]=269.0.

87.41-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-thiophen-2-yl-1H-pyrimidin-2-one

0.21 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-thiophen-2-yl-1H-pyrimidin-2-one fromExample 87.3 (1.86 mmol, 0.50 g) with2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (1.87 mmol, 0.49 g;prepared as described in DE 19735410).

¹H NMR (400 MHz, DMSO-d₆) δ (ppm: 8.22 (1H, d), 8.04 (1H, d), 7.88 (1H,d), 7.24 (1H, t), 7.01 (1H, d), 6.41 (1H, s), 3.87 (2H, t), 3.57 (4H, sbr.), 2.45 (2H, t), 2.39 (4H, s br.), 2.34 (2H, t), 1.76-1.55 (4H, m),1.46 (2H, quint.), 1.25 (9H, s), 0.89 (3H, t).

Example 881-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-thiophen-2-yl-1H-pyrimidin-2-one

0.21 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-thiophen-2-yl-1H-pyrimidin-2-one fromExample 87.3 (1.86 mmol, 0.50 g) with2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (1.87 mmol,0.54 g; prepared as described in DE 19735410).

¹H NMR (400 MHz, DMSO-d₆) δ (ppm: 8.23 (1H, d), 8.03 (1H, s), 7.88 (1H,d), 7.23 (1H, s), 7.02 (2H, s), 3.87 (2H, t), 3.70 (4H, s br.), 2.41(4H, s br.), 2.33 (2H, t), 1.74 (2H, quint.), 1.44 (2H, quint.), 1.28(9H, s).

Example 891-[4-(4-Azetidin-1-yl-2-oxo-2H-pyrimidin-1-yl)butyl]-4-(2-tert-butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-iumfumarate 89.11-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-thioxo-3,4-dihydro-1H-pyrimidin-2-one

The title compound was obtained in the manner described in J. Med. Chem.1984, 27, 1470-80, p. 1478, Example 8b, starting from1-(4-{4-[2-tert-butyl-6-(trifluoromethyl)-pyrimidin-4-yl]piperazin-1-yl}butyl)-4-hydroxypyrimidin-2(1H)-onefrom Example 13.

89.21-[4-(4-Azetidin-1-yl-2-oxo-2H-pyrimidin-1-yl)butyl]-4-(2-tert-butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-iumfumarate

0.07 g of the title compound was obtained in analogy to Example 48 byreacting1-{4-[4-(2-tert-butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-thioxo-3,4-dihydro-1H-pyrimidin-2-one(0.21 mmol, 0.12 g) with azetidine (5.25 mmol, 0.30 g).

ESI-MS: [M+K⁺]=532.3, 495.2, [M+H⁺]=494.2.

Example 904-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(2-oxo-4-pyrrolidin-1-yl-2H-pyrimidin-1-yl)butyl]piperazin-1-iumfumarate

0.05 g of the title compound was obtained in analogy to 48 by reacting1-{4-[4-(2-tert-butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-thioxo-3,4-dihydro-1H-pyrimidin-2-onefrom Example 89.1 (0.21 mmol, 0.12 g) with pyrrolidine (5.20 mmol, 0.37g).

ESI-MS: [M+H⁺]=508.3, 254.6.

Example 914-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(2-oxo-4-piperidin-1-yl-2H-pyrimidin-1-yl)butyl]piperazin-1-iumfumarate

0.06 g of the title compound was obtained in analogy to Example 48 byreacting1-{4-[4-(2-tert-butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-thioxo-3,4-dihydro-1H-pyrimidin-2-one(0.21 mmol, 0.12 g) with piperidine (5.05 mmol, 0.43 g).

ESI-MS: [M+Na⁺]=544.3, 523.3, [M+H⁺]=522.3, 261.6.

Example 924-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(2-oxo-4-thiophen-3-yl-2H-pyrimidin-1-yl)butyl]piperazin-1-iumfumarate 92.1 2-Chloro-4-thiophen-3-ylpyrimidine

1.25 g of 2-chloro-4-thiophen-3-ylpyrimidine were obtained in analogy toExample 24.1 by reacting 2,4-dichloropyrimidine (7.82 mmol, 1.16 g) withthiophene-3-boronic acid (7.82 mmol, 1.00 g).

ESI-MS: [M+H⁺]=196.9.

92.2 4-Thiophen-3-yl-1H-pyrimidin-2-one

1.30 g of 4-thiophen-3-yl-1H-pyrimidin-2-one were obtained in analogy toExample 24.2 from 2-chloro-4-thiophen-3-ylpyrimidine from Example 92.1(5.26 mmol, 1.15 g).

ESI-MS: [M+H⁺]=179.1.

92.3 1-(4-Chlorobutyl)-4-thiophen-3-yl-1H-pyrimidin-2-one

0.25 g of 1-(4-chlorobutyl)-4-thiophen-3-yl-1H-pyrimidin-2-one wasobtained in analogy to Example 24.3 by reacting4-thiophen-3-yl-1H-pyrimidin-2-one from Example 92.2 (5.81 mmol, 1.15 g)with 1-bromo-4-chlorobutane.

ESI-MS: [M+H⁺]=269.0.

92.44-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(2-oxo-4-thiophen-3-yl-2H-pyrimidin-1-yl)butyl]piperazin-1-iumfumarate

0.12 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-thiophen-3-yl-1H-pyrimidin-2-one fromExample 92.3 (0.37 mmol, 0.11 g) with2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.38 mmol,0.11 g; prepared as described in DE 19735410).

ESI-MS: 522.2, [M+H⁺]=521.3, 261.1.

Example 931-{4-[4-(2-tert-Butyl-6-propylpyrimidin-4-yl)piperazin-1-yl]butyl}-4-thiophen-3-yl-1H-pyrimidin-2-one

0.08 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-thiophen-3-yl-1H-pyrimidin-2-one fromExample 92.3 (0.40 mmol, 0.12 g) with2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.42 mmol, 0.11 g;prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=495.4, 248.1.

Example 944-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(4-cyclopropyl-2-oxo-2H-pyrimidin-1-yl)butyl]piperazin-1-iumacetate 94.1 1-Cyclopropyl-3,3-dimethoxypropan-1-one

6.50 g of 1-cyclopropyl-3,3-dimethoxypropan-1-one were obtained inanalogy to Helv. Chim. Acta 2002, 85, 2926-29 (Example 6, p. 2928) byreacting 1-cyclopropyl methyl ketone (149.79 mmol, 12.60 g) with methylformate (300.0 mmol, 18.02 g).

94.2 4-Cyclopropyl-1H-pyrimidin-2-one

0.11 g of 4-cyclopropyl-1H-pyrimidin-2-one was obtained in analogy toExample 8.1 from 1-cyclopropyl-3,3-dimethoxypropan-1-one from Example94.1 (12.64 mmol, 2.00 g) with urea.

94.3 1-(4-Chlorobutyl)-4-cyclopropyl-1H-pyrimidin-2-one

0.05 g of 1-(4-chlorobutyl)-4-cyclopropyl-1H-pyrimidin-2-one wasobtained in analogy to Example 5.2.1 by reacting4-cyclopropyl-1H-pyrimidin-2-one from Example 94.2 (0.81 mmol, 0.11 g)with 1-bromo-4-chlorobutane.

94.44-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(4-cyclopropyl-2-oxo-2H-pyrimidin-1-yl)butyl]piperazin-1-iumacetate

0.02 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-cyclopropyl-1H-pyrimidin-2-one (0.22 mmol,50.0 mg) with 2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine(0.21 mmol, 0.06 g; prepared as described in DE 19735410).

ESI-MS: [M+Na⁺]=501.2, 480.2, [M+H⁺]=479.2, 240.1.

Example 954-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(4-ethyl-2-oxo-2H-pyrimidin-1-yl)butyl]piperazin-1-iumfumarate 95.1 1,1-Dimethoxypentan-3-one

6.60 g of 1,1-dimethoxypentan-3-one were obtained in analogy to Helv.Chim. Acta 2002, 85, 2926-29 (Example 6, p. 2928) by reacting ethylmethyl ketone (161.98 mmol, 11.68 g) with methyl formate (324.66 mmol,19.50 g).

95.2 4-Ethyl-1H-pyrimidin-2-one

2.90 g of 4-ethyl-1H-pyrimidin-2-one were obtained in analogy to Example8.1 by reacting 1,1-dimethoxy-pentan-3-one from Example 95.1 (29.55mmol, 4.80 g) with urea.

ESI-MS: [M+H⁺]=125.1.

95.3 1-(4-Chlorobutyl)-4-ethyl-1H-pyrimidin-2-one

0.22 g of 1-(4-chlorobutyl)-4-ethyl-1H-pyrimidin-2-one was obtained inanalogy to Example 5.2.1 by reacting 4-ethyl-1H-pyrimidin-2-one fromExample 95.2 (23.36 mmol, 2.90 g) with 1-bromo-4-chlorobutane.

ESI-MS: [M+H⁺]=215.1.

95.44-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(4-ethyl-2-oxo-2H-pyrimidin-1-yl)butyl]piperazin-1-iumfumarate

0.09 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-ethyl-1H-pyrimidin-2-one from Example 95.3(0.47 mmol, 0.10 g) with2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.47 mmol,0.14 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=467.3, 234.1.

Example 964-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(4-ethyl-2-oxo-2H-pyrimidin-1-yl)butyl]piperazin-1-iumfumarate

12.0 mg of the title compound were obtained in analogy to Example 5.2.2by reacting 1-(4-chlorobutyl)-4-ethyl-1H-pyrimidin-2-one from Example95.3 (0.33 mmol, 0.07 g) with2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.34 mmol, 0.09 g;prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=441.4, 221.1.

Example 974-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(4-isopropyl-2-oxo-2H-pyrimidin-1-yl)butyl]piperazin-1-iumfumarate 97.1 1,1-Dimethoxy-4-methylpentan-3-one

7.80 g of the title compound were obtained in analogy to Helv. Chim.Acta 2002, 85, 2926-29 (Example 6, p. 2928) by reacting3-methylbutan-2-one (186.68 mmol, 16.08 g) with methyl formate (373.04mmol, 22.40 g).

97.2 4-Isopropyl-1H-pyrimidin-2-one

3.30 g of 4-isopropyl-1H-pyrimidin-2-one were obtained in analogy toExample 8.1 from 1,1-dimethoxy-4-methylpentan-3-one from Example 97.1(43.69 mmol, 7.00 g) with urea.

ESI-MS: [M+H⁺]=139.1.

97.3 1-(4-Chlorobutyl)-4-isopropyl-1H-pyrimidin-2-one

0.90 g of 1-(4-chlorobutyl)-4-isopropyl-1H-pyrimidin-2-one was obtainedin analogy to Example 5.2.1 by reacting 4-isopropyl-1H-pyrimidin-2-onefrom Example 97.2 (14.47 mmol, 2.00 g) with 1-bromo-4-chlorobutane.

ESI-MS: 231.1, [M+H⁺]=229.1.

97.44-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(4-isopropyl-2-oxo-2H-pyrimidin-1-yl)butyl]piperazin-1-iumfumarate

0.27 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-isopropyl-1H-pyrimidin-2-one from Example97.3 (1.09 mmol, 0.25 g) with2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (1.09 mmol,0.32 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=481.2, 241.1.

Example 984-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(4-isopropyl-2-oxo-2H-pyrimidin-1-yl)butyl]piperazine1-fumarate

0.35 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-isopropyl-1H-pyrimidin-2-one from Example97.3 (1.09 mmol, 0.25 g) with2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (1.11 mmol, 0.29 g;prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=455.4, 228.1.

Example 994-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(4-cyclohexyl-2-oxo-2H-pyrimidin-1-yl)butyl]piperazin-1-iumfumarate 99.1 1-Cyclohexyl-3,3-dimethoxypropan-1-one

1.50 g of the title compound were obtained in analogy to Helv. Chim.Acta 2002, 85, 2926-29 (Example 6, p. 2928) by reacting1-cyclohexylethanone (150.55 mmol, 19.00 g) with methyl formate (300.05mmol, 18.02 g).

99.2 4-Cyclohexyl-1H-pyrimidin-2-one

0.62 g of the title compound was obtained in analogy to Example 8.1 byreacting 1-cyclohexyl-3,3-dimethoxypropan-1-one from Example 99.1 (6.99mmol, 1.40 g) with urea.

ESI-MS: [M+H⁺]=179.1.

99.3 1-(4-Chlorobutyl)-4-cyclohexyl-1H-pyrimidin-2-one

0.65 g of 1-(4-chlorobutyl)-4-cyclohexyl-1H-pyrimidin-2-one was obtainedin analogy to Example 5.2.1 by reacting 4-cyclohexyl-1H-pyrimidin-2-onefrom Example 99.2 (2.55 mmol, 0.46 g) with 1-bromo-4-chlorobutane.

ESI-MS: 271.1, [M+H⁺]=269.1.

99.44-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)-1-[4-(4-cyclohexyl-2-oxo-2H-pyrimidin-1-yl)butyl]piperazin-1-iumfumarate

0.40 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-cyclohexyl-1H-pyrimidin-2-one from Example99.3 (1.12 mmol, 0.30 g) with2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (1.14 mmol,0.33 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=521.3, 261.1.

Example 1004-(2-tert-Butyl-6-propylpyrimidin-4-yl)-1-[4-(4-cyclohexyl-2-oxo-2H-pyrimidin-1-yl)butyl]piperazin-1-iumfumarate

0.23 g of the title compound was obtained in analogy to Example 5.2.2 byreacting 1-(4-chlorobutyl)-4-cyclohexyl-1H-pyrimidin-2-one from Example99.3 (0.82 mmol, 0.22 g) with2-tert-butyl-4-piperazin-1-yl-6-propylpyrimidine (0.82 mmol, 0.22 g;prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=495.4, 248.3.

Example 1011-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-5-phenyl-1H-pyrimidin-2-one101.1 5-Phenyl-1H-pyrimidin-2-one

40.0 mg of 5-phenyl-1H-pyrimidin-2-one were obtained in analogy to themethod in Tetrahedron 1997, 53, 14437-50 from 5-bromo-1H-pyrimidin-2-one(2.29 mmol, 0.40 g).

ESI-MS: [M+H⁺]=173.1.

101.21-(4-Chlorobutyl)-5-phenyl-1H-pyrimidin-2-one

0.03 g of 1-(4-chlorobutyl)-5-phenyl-1H-pyrimidin-2-one was obtained inanalogy to Example 5.2.1 by reacting 5-phenyl-1H-pyrimidin-2-one fromExample 101.1 (0.23 mmol, 0.04 g) with 1-bromo-4-chlorobutane.

ESI-MS: [M+H⁺]=263.1.

101.31-{4-[4-(2-tert-Butyl-6-trifluoromethylpyrimidin-4-yl)piperazin-1-yl]butyl}-5-phenyl-1H-pyrimidin-2-one

8.0 mg of the title compound were obtained in analogy to Example 5.2.2by reacting 1-(4-chlorobutyl)-5-phenyl-1H-pyrimidin-2-one from Example101.3 (0.10 mmol, 0.03 g) with2-tert-butyl-4-piperazin-1-yl-6-trifluoromethylpyrimidine (0.09 mmol,0.03 g; prepared as described in DE 19735410).

ESI-MS: [M+H⁺]=515.3, 258.2.

Example 1021-{4-[4-(3,4-Dimethoxyphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(3,4-dimethoxyphenyl)-piperazine.

ESI-MS: [M+H⁺]=403.2.

Example 1031-{4-[4-(2-Fluorophenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(2-fluorophenyl)piperazine.

ESI-MS: [M+H⁺]=361.1.

Example 1041-{4-[4-(4-Fluorophenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(4-fluorophenyl)piperazine.

ESI-MS: [M+H⁺]=361.0.

Example 1051-{4-[4-(2-Methoxyphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(2-methoxyphenyl)piperazine.

ESI-MS: [M+H⁺]=373.0.

Example 1061-{4-[4-(4-Methoxyphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(4-methoxyphenyl)piperazine.

ESI-MS: [M+H⁺]=373.1.

Example 1071-{4-[4-(2-Ethoxyphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(2-ethoxyphenyl)piperazine.

ESI-MS: [M+H⁺]=387.0, 234.9.

Example 1082-{4-[4-(5-Methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)butyl]piperazin-1-yl}nicotinonitrile

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with2-piperazin-1-ylnicotinonitrile.

ESI-MS: [2M+H⁺]=737.2, [M+H⁺]=369.1.

Example 1091-{4-[4-(2,4-Dimethoxyphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(2,4-dimethoxyphenyl)piperazine.

ESI-MS: [M+H⁺]=403.2.

Example 1101-{4-[4-(3,4-Difluorophenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(3,4-difluorophenyl)piperazine.

ESI-MS: [2M+H⁺]=757.1, [M+H⁺]=379.0.

Example 1115-Methyl-1-[4-(4-(o-tolyl)piperazin-1-yl)butyl]-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(o-tolyl)piperazine.

ESI-MS: [M+H⁺]=357.1.

Example 1125-Methyl-1-{4-[4-(6-methylpyridin-2-yl)piperazin-1-yl]butyl}-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(6-methylpyridin-2-yl)piperazine.

ESI-MS: [2M+H⁺]=715.2, [M+H⁺]=358.0, 134.9.

Example 1131-{4-[4-(2,5-Dimethoxyphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(2,5-dimethoxyphenyl)piperazine.

ESI-MS: [M+H⁺]=417.2, 264.9, 151.2.

Example 1145-Methyl-1-{4-[4-(3-methylpyridin-2-yl)piperazin-1-yl]butyl}-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(3-methylpyridin-2-yl)piperazine.

ESI-MS: [M+H⁺]=358.1.

Example 1155-Methyl-1-{4-[4-(4-methylpyridin-2-yl)piperazin-1-yl]butyl}-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(4-methylpyridin-2-yl)piperazine.

ESI-MS: [M+H⁺]=358.0, 134.9.

Example 1164-{4-[4-(5-Methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)butyl]piperazin-1-yl}benzonitrile

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with4-piperazin-1-ylbenzonitrile.

ESI-MS: [2M+H⁺]=735.1, [M+H⁺]=368.1.

Example 1171-{4-[4-(5-Chloro-2-methoxyphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(5-chloro-2-methoxyphenyl)piperazine.

ESI-MS: [M+H⁺]=407.0, 226.8.

Example 1181-{4-[4-(4-tert-Butylphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(4-tert-butylphenyl)piperazine.

ESI-MS: [M+H⁺]=399.3, 218.9.

Example 1191-{4-[4-(3,5-Dichlorophenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(3,5-dichlorophenyl)piperazine.

ESI-MS: [M+H⁺]=411.2, 230.8.

Example 1202-{4-[4-(5-Methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)butyl]piperazin-1-yl}benzonitrile

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with2-(piperazin-1-yl)benzonitrile.

ESI-MS: [M+H⁺]=368.1, 187.9.

Example 1211-{4-[4-(4-Chloro-3-trifluoromethylphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(4-chloro-3-trifluoromethylphenyl)piperazine.

ESI-MS: [M+H⁺]=445.0, 403.0, 292.8, 264.8.

Example 1221-{4-[4-(2,6-Dimethylphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(2,6-dimethylphenyl)piperazine.

ESI-MS: [M+H⁺]=371.0, 190.9, 147.9.

Example 1231-{4-[4-(2,4-Dichlorophenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(2,4-dichlorophenyl)piperazine.

ESI-MS: [M+H⁺]=411.0, 230.8, 187.7.

Example 1245-Methyl-1-{4-[4-(3-trifluoromethylpyridin-2-yl)piperazin-1-yl]butyl}-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(3-trifluoromethylpyridin-2-yl)piperazine.

ESI-MS: [M+H⁺]=412.2, 259.9, 231.8, 188.8.

Example 1251-{4-[4-(3,5-Bis-trifluoromethylphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(3,5-bis-trifluoromethylphenyl)piperazine.

ESI-MS: [M+H⁺]=479.0, 340.2, 298.8.

Example 1265-Methyl-1-[4-(4-(p-tolyl)piperazin-1-yl)butyl]-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(p-tolyl)piperazine (1-(4-methylphenyl)piperazine).

ESI-MS: [M+H⁺]=357.0, 204.9, 176.9.

Example 1271-{4-[4-(2-Chlorophenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(2-chlorophenyl)piperazine.

ESI-MS: [M+H⁺]=376.9, 196.8.

Example 1281-{4-[4-(2,3-Dimethylphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(2,3-dimethylphenyl)piperazine.

ESI-MS: [M+H⁺]=371.0, 190.9.

Example 1295-Methyl-1-{4-[4-(3-trifluoromethylphenyl)piperazin-1-yl]butyl}-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(3-trifluoromethylphenyl)piperazine.

ESI-MS: [M+H⁺]=411.1, 271.9, 230.8.

Example 1301-{4-[4-(4-Chlorophenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(4-chlorophenyl)piperazine.

ESI-MS: [M+H⁺]=376.9, 196.8, 153.8.

Example 1311-{4-[4-(2,4-Difluorophenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(2,4-difluorophenyl)piperazine.

ESI-MS: [M+H⁺]=379.0, 198.9.

Example 1321-{4-[4-(3,5-Dimethylphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(3,5-dimethylphenyl)piperazine.

ESI-MS: [2M+H⁺]=741.2, [M+H⁺]=371.0, 190.9, 147.9.

Example 1331-{4-[4-(4-Chloro-2-fluorophenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(4-chloro-2-fluorophenyl)piperazine.

ESI-MS: [M+H⁺]=395.0, 214.8.

Example 1341-{4-[4-(3,5-Dimethoxyphenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(3,5-dimethoxyphenyl)piperazine.

ESI-MS: [M+H⁺]=403.2, 222.9.

Example 1351-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butyl}-5-methyl-1H-pyrimidine-2,4-dione

The title compound was obtained in analogy to Example 5.2.2 by reacting1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one with1-(2,3-dichlorophenyl)piperazine.

ESI-MS: [M+H⁺]=410.9, 230.8.

Examples of pharmaceutical administration forms

A) Tablets Tablets of the following composition are compressed in atablet press in a conventional way: 40 mg of substance of example 2 120mg of corn starch 13.5 mg of gelatin 45 mg of lactose 2.25 mg ofAerosil ® (chemically pure silica in submicroscopically finedistribution) 6.75 mg of potato starch (as 6% strength paste)

B) Sugar-coated tablets 20 mg of substance of example 2 60 mg of corecomposition 70 mg of sugar-coating composition

The core composition consists of 9 parts of corn starch, 3 parts oflactose and 1 part of vinylpyrrolidone/vinyl acetate 60:40 copolymer.The sugar-coating composition consists of 5 parts of sucrose, 2 parts ofcorn starch, 2 parts of calcium carbonate and 1 part of talc. Thesugar-coated tablets produced in this way are subsequently provided withan enteric coating.

Biological Investigations—Receptor Binding Studies:

The substance to be tested was dissolved either in methanol/Chremophor®(BASF-AG) or in dimethyl sulfoxide and then diluted with water to thedesired concentration.

Dopamine D₃ Receptor:

The mixture (0.250 ml) is composed of membranes from ˜10⁶ HEK-293 cellswith stably expressed human dopamine D3 receptors, 0.1 nM[¹²⁵I]-iodosulpride and incubation buffer (total binding) or withadditional test substance (inhibition plot) or 1 μM spiperone(nonspecific binding). Triplicate mixtures were carried out.

The incubation buffer contained 50 mM Tris, 120 mM NaCl, 5 mM KCl, 2 mMCaCl₂, 2 mM MgCl₂ and 0.1% bovine serum albumin, 10 μM quinolone, 0.1%ascorbic acid (prepared fresh each day). The buffer was adjusted to pH7.4 with HCl.

Dopamine D_(2L) Receptor:

The mixture (1 ml) was composed of membranes from ˜10⁶ HEK-293 cellswith stably expressed human dopamine D_(2L) receptors (long isoform) and0.01 nM [¹²⁵I]-iodospiperone and incubation buffer (total binding) orwith additional test substance (inhibition plot) or 1 μM haloperidol(nonspecific binding). Triplicate mixtures were carried out.

The incubation buffer contained 50 mM Tris, 120 mM NaCl, 5 mM KCl, 2 mMCaCl₂, 2 mM MgCl₂ and 0.1% bovine serum albumin. The buffer was adjustedto pH 7.4 with HCl.

Measurement and Evaluation:

After incubation at 25° C. for 60 minutes, the mixtures were filteredunder vacuum through Whatman GF/B glass fiber filters using a cellharvester. The filters were transferred by a filter transfer system intoscintillation vials. After addition of 4 ml of Ultima Gold® (Packard),the samples were shaken for one hour and then the radioactivity wascalculated in a beta counter (Packard, Tricarb 2000 or 2200CA). The cpvalues were converted into dpm by means of a standard quench series withthe aid of the instrument's own program.

Evaluation of the inhibition plots took place by iterative nonlinearregression analysis using the Statistical Analysis System (SAS) similarto the “LIGAND” program described by Munson and Rodbard.

In these assays, the inventive compounds show very good affinities forthe D₃ receptor (<100 nM, frequently <50 nM) and bind selectively to theD₃ receptor. The results of the binding assays are indicated in table 2.

TABLE 2 Example K_(i) (D₃) [nM] Selectivity D₃ vs. D₂L* 2 3.23 88 5 1.30246 6 31.2 35 8 4.4 71 9 0.74 53 10 1.75 97 11 3.14 65 12 3.44 63 131.88 104 14 2.62 82 15 14.5 64 16 2.99 201 17 0.71 134 18 4.78 99 191.44 96 20 1.87 108 21 1.94 96 22 1.16 77 23 1.51 63 24 1.38 122 2510.40 34 26 8.10 55 27 11.8 52 29 7.64 67 33 0.70 42 35 4.96 116 36 3.82209 37 3.24 126 38 5.33 103 39 6.09 66 40 2.12 67 41 5.78 62 44 0.63 15845 4.99 37 46 5.41 43 47 4.87 51 49 0.54 86 50 0.72 77 52 2.28 97 532.32 56 54 9.25 52 55 5.44 119 56 1.02 134 57 0.96 111 59 1.80 44 604.33 91 61 5.84 28 62 11.0 49 63 2.97 65 64 2.57 57 65 3.31 62 66 13.537 67 10.1 39 69 1.80 54 70 10.0 30 71 7.44 37 72 1.49 54 73 9.30 31 741.52 53 75 2.30 80 76 3.03 103 77 0.74 150 78 0.32 48 79 0.86 30 81 2.5694 82 0.31 54 83 1.66 89 84 0.75 63 85 7.36 35 86 2.44 43 87 0.97 31 924.56 31 93 0.65 40 94 4.28 36 95 6.53 45 97 4.26 58 98 1.62 59 99 4.8257 100 1.38 51 111 6.80 30 119 0.46 65 125 6.8 63 127 1.5 45 128 2.4 55129 1.3 48 131 25.7 30 132 5.5 34 134 13.1 55 135 0.27 87*K_(i)(D₃)/K_(i)(D_(2L))Inhibition of Mitochondrial Respiration:

The inhibition of mitochondrial respiration by the compounds of theinvention was ascertained by determining the oxygen consumption ofmitochondria associated with the production of ATP in a manner known perse (see Donelly et al. Arch. Toxicol. 1994. 68. p. 110. Wong et al.Toxicol. Lett. 2000. 116(3). p. 171-81. Devi et al. Life Sci. 1997.60(11). p. 849-55).

The investigation was carried out using a Strathkelvin measuringinstrument to determine dissolved O₂, using the recording and analysissoftware belonging thereto.

For this purpose, initially the O₂ electrodes of the measuringinstrument were equilibrated in Hudson's buffer (140 mM KCl/5 mMKH₂PO₄/20 mM MOPS/pH=7.2) and then with aqueous sodium sulfite solution(20 g/l). The electrodes were rinsed with water (double-distilled) afterequilibration before each measurement.

In a reaction vessel with 6 separate chambers, each equipped withmagnetic stirring bars and thermostated at 37° C., 1.4 ml of Hudson'sbuffer and then 7.5 μl of a solution of the active substance in dimethylsulfoxide (normally in a concentration range from 0.8 to 40 mM) were putinto chambers 2 to 6 of the investigation vessel, and 7.5 μl of DMSOwithout active substance were put into chamber 1. A suspension offreshly isolated functional mitochondria was put into each chamber in anamount of 1.5 mg of total protein (per chamber). The electrode was theninserted into the respective chamber, the electrodes were allowed toequilibrate for 30-60 s, and then 25 μL of succinic acid solution (300mM) were added and equilibrated for 60-120 s. 2 μL of adenosinediphosphate solution (200 mM) were added thereto and equilibrated forsome minutes, and then 1 μL of 2,4-dinitrophenol solution (300 mM) wasadded and at least one further minute was allowed to elapse. The oxygenconcentration was then recorded. The concentration necessary to inhibitoxygen uptake (IC₅₀ value) was ascertained therefrom.

The compounds of the invention inhibit mitochondrial respiration only ata high concentration ordinarily above 50 μM, in particular >100 μM (IC₅₀values) and specifically >200 μM.

Investigation of the Nonselective Protein Binding

2 concentrations of the substance to be tested in plasma areinvestigated. 100 μl of a stock solution (1 mg/ml) are spiked in 4.9 mlof plasma for the 20 000 ng/ml concentration, and 25 μl of the stocksolution in 4.975 ml of plasma for the 5000 ng/ml concentration. In eachcase, 1 ml portions of the spiked plasma of each concentration areweighed into ultracentrifugation tubes for a triplicate determination,and centrifuged at 80 000×g and 15° C. for 18 h. 5 samples each of 100μl of the respective supernatant is taken directly from the surface ofeach tube, pipetted into Eppendorf tubes, mixed with 100 μl ofacetonitrile/water mixture (1:1) and frozen at −20° C. until analyzed.The remaining 500 μl of plasma with the pellet are taken up in 500 μl ofacetonitrile/water mixture (1:1) and frozen until analyzed.

Analysis takes place by LC/MS/MS. For the evaluation, the concentrationsof the first 2×100 μl of the plasma supernatant are related to the totalconcentration recovered.

The compounds of the invention are distinguished by a comparatively lowprotein binding. They therefore show a higher free concentration in theplasma and ought to show better tolerability because of a more uniformplasma level (less release from plasma protein binding, e.g. throughphysical activity or medicament interaction).

1. A pyrimidin-2-one compound of the formula I, or a tautomer thereof,

in which A is —(CH₂)_(n)—, in which n is 4, 5, or 6, or istrans-CH₂—CH═CH—CH₂—, trans-CH₂—C(CH₃)═CH—CH₂—, —CH₂—CH(CH₃)—CH₂—CH₂—,or —CH₂—CH₂—CH₂—CH(CH)₃—, B is a radical of the formula:

in which X is CH₂ or N, and Y is CH₂ or CH₂CH₂, or X—Y together may alsobe C═CH, C═CH—CH₂ or CH—CH═CH, R¹ is selected from OR^(3a), NR⁴R⁵, SR⁶,C₃-C₆-cycloalkyl, C₁-C₄-alkyl which is optionally substituted by OH,C₁-C₄-alkoxy, halogen or phenyl, 5- or 6-membered aromatic heterocyclylhaving 1, 2 or 3 heteroatoms selected from O, S and N, which may besubstituted by one or two radicals which are selected independently ofone another from C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁴R⁵, CN, OH,C₁-C₂-fluoroalkyl or halogen, and phenyl which may be substituted by oneor two radicals which are selected independently of one another fromC₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁴R⁵, OH, CN, C₁-C₂-fluoroalkyl or halogenR² is selected from H, C₁-C₄-alkyl, halogen, C₁-C₂-fluoroalkyl andcyano, Ar is an aromatic radical which is selected from phenyl, pyridyl,pyrimidinyl and triazinyl, where the aromatic radical may have 1, 2 or 3substituents which are selected independently of one another fromC₁-C₆-alkyl which is optionally substituted by OH, C₁-C₄-alkoxy, halogenor phenyl, or C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl,C₅-C₁₀-bicycloalkyl, C₆-C₁₀-tricycloalkyl, where the last three groupsmentioned may optionally be substituted by halogen or C₁-C₄-alkyl, orhalogen, CN, OR^(3c), NR⁴R⁵, NO₂, SR⁶, SO₂R⁶, SO₂NR⁴R⁵, COOR⁷, COR⁸, 5-or 6-membered heterocyclyl having 1, 2 or 3 heteroatoms selected from O,S and N, and phenyl, where phenyl and heterocyclyl optionally have oneor two substituents which are selected independently of one another fromC₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁴R⁵, CN, C₁-C₂-fluoroalkyl and halogen, andwhere 2 substituents bonded to adjacent C atoms of the aromatic radicalmay together be C₃- or C₄-alkylene, or may together with the C atoms towhich they are bonded be a fused-on, unsaturated 5 or 6-memberedcarbocycle or a 5- or 6-membered heterocycle having 1 or 2 nitrogenatoms as ring members, R³, R^(3a), R^(3b), R^(3c), R^(3d), R⁴, R⁵, R⁶,R⁷ and R⁸ are independently of one another H, C₁-C₆-alkyl which isoptionally substituted by OH, C₁-C₄-alkoxy or phenyl, or C₁-C₆-haloalkylor phenyl, where R⁵ may also be a group COR⁹ where R⁹ is hydrogen,C₁-C₄-alkyl or phenyl which is optionally substituted by one or tworadicals which are selected independently of one another fromC₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁴R⁵, CN, C₁-C₂-fluoroalkyl or halogen,where R⁴ with R⁵ may also form together with the nitrogen atom to whichthey are bonded a 4-, 5- or 6-membered saturated or unsaturatedheterocycle which may optionally have a further heteroatom selected fromO, S and NR¹⁰ as ring member, where R¹⁰ is hydrogen or C₁-C₄-alkyl, andwhere the heterocycle may optionally carry 1, 2, 3 or 4 C₁-C₄-alkylgroups, or a physiologically tolerated salt thereof.
 2. A pyrimidinonecompound as claimed in claim 1, in which Ar is selected from a radicalof the general formula:

in which at least one of the variables D¹ to D³ is N and the othervariables D¹ to D³ are CH, and R^(a) and R^(b) have independently of oneanother the following meanings: OR^(3c), NR⁴R⁵, CN, C₁-C₆-alkyl which isoptionally substituted by OH, C₁-C₄-alkoxy, halogen or phenyl, orC₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₅-C₁₀-bicycloalkyl,C₆-C₁₀-tricycloalkyl, where the last three groups mentioned mayoptionally be substituted by halogen or C₁-C₄-alkyl, or halogen, CN,C₁-C₄-alkoxy, 5- or 6-membered heterocyclyl having 1, 2 or 3 heteroatomsselected from O, S and N, and phenyl, where phenyl and heterocyclyloptionally have one or two substituents which are selected independentlyof one another from C₁-C₄-alkyl, C₁-C₄-alkoxy, NR⁴R⁵, CN,C₁-C₂-fluoroalkyl and halogen.
 3. A pyrimidinone compound as claimed inclaim 2, in which R^(a) is C₁-C₆-alkyl and R^(b) is selected fromC₁-C₆-alkyl, C₃-C₆-cycloalkyl and C₁-C₂-fluoroalkyl.
 4. A pyrimidinonecompound as claimed in claim 1, in which R¹ is OR^(3a) in particular OH.5. A pyrimidinone compound as claimed in claim 1, in which R² isselected from H, C₁-C₄-alkyl, halogen or cyano.
 6. A pyrimidinonecompound as claimed in claim 1, in which A is a group of the formula—(CH₂)_(n)— in which n is
 4. 7. A pyrimidinone compound as claimed inclaim 1, in which B in formula I is selected from bivalent radicals ofthe general formulae:


8. A pyrimidinone compound of the formula I.1, or a tautomer thereof,

in which Ar, R¹ and R² have the meanings stated in claim 1, n is 4, 5 or6, or a physiologically tolerated acid addition salt thereof.
 9. Apyrimidinone compound as claimed in claim 8, in which Ar is selectedfrom a radical of the general formula:

in which at least one of the variables D¹ to D³ is N and the othervariables D¹ to D³ are CH, R^(b) is C₁-C₆-alkyl, and R^(a) is selectedfrom C₁-C₆-alkyl, C₃-C₆-cycloalkyl and C₁-C₂-fluoroalkyl.
 10. Apyrimidinone compound as claimed in claim 9, in which D¹ and D² are Nand D³ is CH.
 11. A pyrimidinone compound as claimed in claim 8, inwhich R¹ is selected from C₁-C₄-alkyl, C₃-C₆-cycloalkyl, OR^(3a), inwhich R^(3a) has the aforementioned meanings, and phenyl which may besubstituted by one or two radicals which are selected independently ofone another from C₁-C₄-alkyl, C₁-C₄-alkoxy, OH, CN, C₁-C₂-fluoroalkyl orhalogen.
 12. A pyrimidinone compound as claimed in claim 11, in which R¹is OR^(3a) and in particular OH.
 13. A pyrimidinone compound as claimedin claim 11, in which R¹ is C₁-C₄-alkyl and in particular methyl.
 14. Apharmaceutical composition comprising at least one compound as claimedin claim 1 and/or the acid addition salt thereof, where appropriatetogether with physiologically acceptable carriers and/or excipients. 15.A method of treating Parkinson's disease, anxiety states, or addictionin a patient in need thereof comprising administering an effectiveamount of at least one compound of claim
 1. 16. A method of treatingschizophrenia and/or depression in a patient in need thereof comprisingadministering an effective amount of at least one compound of claim 1.17. A compound of claim 1 having the general formula I.1a,

wherein R¹ is OH, R² is H, R^(a) is CHF₂ and A′ is (CH₂)₄, or R¹ is OH,R² is H, R^(a) is CF₃ and A′ is (CH₂)₄, or R¹ is OH, R² is CH₃, R^(a) isCF₃ and A′ is (CH₂)₄, or R¹ is OH, R² is F, R^(a) is CF₃ and A′ is(CH₂)₄ or R¹ is OH, R² is H, R^(a) is CH₂CH₂CH₃ and A′ is (CH₂)₄ or R¹is OH, R² is CH₃, R^(a) is CH₂CH₂CH₃ and A′ is (CH₂)₄.
 18. Apharmaceutical composition comprising at least one compound as claimedin claim 17 and/or the acid addition salt thereof, where appropriatetogether with physiologically acceptable carriers and/or excipients. 19.A method of treating Parkinson's disease, anxiety states, or addictionin a patient in need thereof comprising administering an effectiveamount of at least one compound of claim
 17. 20. A method of treatingschizophrenia and/or depression in a patient in need thereof comprisingadministering an effective amount of at least one compound of claim 17.